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Christine B. Ambrosone | Researcher | BCRF

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Learn more about Christine B. Ambrosone at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Christine B. Ambrosone | Researcher | Breast Cancer Research Foundation

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Learn more about Christine B. Ambrosone at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor and Chair
Department of Cancer Prevention and Control
Roswell Park Comprehensive Cancer Center
Buffalo, New York

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Dr. Ambrosone is a Distinguished Professor of Oncology, Chair of the Department of Cancer Prevention and Control, and Senior Vice President for Population Sciences at Roswell Park Comprehensive Cancer Center. She is also co-leader of the CCSG Population Sciences Program. She was formerly a member of NCI’s EPIC Study Section and the ACS’s study section on Carcinogenesis, Nutrition and the Environment, and has served on several special emphasis panels and SPORE reviews.

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Dr. Ambrosone is a Distinguished Professor of Oncology, Chair of the Department of Cancer Prevention and Control, and Senior Vice President for Population Sciences at Roswell Park Comprehensive Cancer Center. She is also co-leader of the CCSG Population Sciences Program. She was formerly a member of NCI’s EPIC Study Section and the ACS’s study section on Carcinogenesis, Nutrition and the Environment, and has served on several special emphasis panels and SPORE reviews. She is former Senior Editor for Cancer Research, was a member of the Board of Scientific Advisors to the Director of the National Cancer Institute until 2012, and served on the Interagency Breast Cancer and Environmental Research Coordinating Committee, established by the US Secretary of Health and Human Services to examine the state of the science on breast cancer and the environment and provide recommendations for future directions in research.

Dr. Ambrosone’s research focuses on both the etiology of breast cancer and factors that influence recurrence and survival after breast cancer diagnosis. She leads a number of studies aimed at determining factors that could account for the high prevalence of more aggressive breast tumors among African-American women, and mechanisms underlying these associations. She is also involved in studies of genetic variability in cancer treatment outcomes (pharmacogenetics) and the potential effects of diet, supplements, and lifestyle factors during and after therapy on breast cancer treatment outcomes.

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Dr. Ambrosone is a Distinguished Professor of Oncology, Chair of the Department of Cancer Prevention and Control, and Senior Vice President for Population Sciences at Roswell Park Comprehensive Cancer Center. She is also co-leader of the CCSG Population Sciences Program. She was formerly a member of NCI’s EPIC Study Section and the ACS’s study section on Carcinogenesis, Nutrition and the Environment, and has served on several special emphasis panels and SPORE reviews. She is former Senior Editor for Cancer Research, was a member of the Board of Scientific Advisors to the Director of the National Cancer Institute until 2012, and served on the Interagency Breast Cancer and Environmental Research Coordinating Committee, established by the US Secretary of Health and Human Services to examine the state of the science on breast cancer and the environment and provide recommendations for future directions in research.

Dr. Ambrosone’s research focuses on both the etiology of breast cancer and factors that influence recurrence and survival after breast cancer diagnosis. She leads a number of studies aimed at determining factors that could account for the high prevalence of more aggressive breast tumors among African-American women, and mechanisms underlying these associations. She is also involved in studies of genetic variability in cancer treatment outcomes (pharmacogenetics) and the potential effects of diet, supplements, and lifestyle factors during and after therapy on breast cancer treatment outcomes.

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Goal: To understand the molecular drivers of aggressive breast cancer in African American women and how these are different in Caucasian women.

Impact: African American women are 40 percent more likely to die of their breast cancer white women. Those diagnosed with breast cancer are more likely to be younger than newly diagnosed white women and more likely to be diagnosed with aggressive disease. While these disparate outcomes are complex and multifactorial, the work of Drs. Ambrosone and Hong is shedding light on molecular factors that contribute to worse mortality rates in Black women compared to white women.

What’s next: Recent findings suggest the immune cells associated with tumors of African American women are defective in their ability to kill cancer cells, suggesting a potential explanation for worse outcomes compared to white women. To further validate their findings, the team will increase the enrollment of Black women in the Women’s Circle of Health Study (WCHS),  to match the same number of white women to black women for a more in-depth analysis.

TNBC is an aggressive disease that disproportionately affects women of African ancestry. Why this disparity exists is not well understood. Drs. Ambrosone and Hong are studying breast tumor tissues from both African American and Caucasian women to identify factors that may influence the incidence of TNBC in African American women.

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Goal: To understand the molecular drivers of aggressive breast cancer in African American women and how these are different in Caucasian women.

Impact: African American women are 40 percent more likely to die of their breast cancer white women. Those diagnosed with breast cancer are more likely to be younger than newly diagnosed white women and more likely to be diagnosed with aggressive disease. While these disparate outcomes are complex and multifactorial, the work of Drs. Ambrosone and Hong is shedding light on molecular factors that contribute to worse mortality rates in Black women compared to white women.

What’s next: Recent findings suggest the immune cells associated with tumors of African American women are defective in their ability to kill cancer cells, suggesting a potential explanation for worse outcomes compared to white women. To further validate their findings, the team will increase the enrollment of Black women in the Women’s Circle of Health Study (WCHS),  to match the same number of white women to black women for a more in-depth analysis.

TNBC is an aggressive disease that disproportionately affects women of African ancestry. Why this disparity exists is not well understood. Drs. Ambrosone and Hong are studying breast tumor tissues from both African American and Caucasian women to identify factors that may influence the incidence of TNBC in African American women.

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Research area: Identifying factors that influence the incidence of triple negative breast cancer (TNBC) in African American women, who are more likely to be diagnosed with this aggressive subtype of breast cancer than Caucasian women.

Impact: While TNBC accounts for less than 20 percent of breast cancer diagnosed in the US, women of African American descent are two times more likely to be diagnosed with TNBC than Caucasian women. Currently, it is not clear what accounts for this disparity. Drs. Ambrosone and Hong are investigating several biological and lifestyle factors that may influence the incidence of TNBC in African American women. This work may provide new insights at the population level into why some women develop more aggressive breast tumors, so that personalized prevention and treatment may be designed.

Current investigation: The team is conduting a series of studies to delineate some of the underlying biological factors of more aggressive breast cancers in African Amerinca women compared to Caucasian women. Current studies include characterizing immune cells in and around breast tumors and the effect of breast feeding on the development of triple negative breast cancer, an aggressive breast cancer that disproportionately affect Black women.

What they’ve learned so far: Drs. Ambrosone and Hong found that tumors from African American women have higher levels of exhausted T cells for all subtypes of breast cancer, and that this is associated with poorer survival. Results from their study on breast feeding has shown that FOXA1–a developmental protein involved in cell differentiation–is supppressed in TNBC and in breast cells of women who do not breast feed after childbirth, suggesting an explanation for the benefit of breast feeding in reducing the risk of breast cancer.

What’s next: In the coming year, the researchers plan to expand the immune cell study with a larger cohort of white women to confirm their initial findings of a prevalence of dysfunctional T-cells in the tumors of Black women compared to white women. With this larger sample size, they will measure a comprehensive panel of proteins in tumors that characterize exhausted immune cells to determine if they are, in fact, more prevalent in tumors from African-American women than Caucasian women and if they are related to poorer survival outcomes in African-American women.

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Research area: Identifying factors that influence the incidence of triple negative breast cancer (TNBC) in African American women, who are more likely to be diagnosed with this aggressive subtype of breast cancer than Caucasian women.

Impact: While TNBC accounts for less than 20 percent of breast cancer diagnosed in the US, women of African American descent are two times more likely to be diagnosed with TNBC than Caucasian women. Currently, it is not clear what accounts for this disparity. Drs. Ambrosone and Hong are investigating several biological and lifestyle factors that may influence the incidence of TNBC in African American women. This work may provide new insights at the population level into why some women develop more aggressive breast tumors, so that personalized prevention and treatment may be designed.

Current investigation: The team is conduting a series of studies to delineate some of the underlying biological factors of more aggressive breast cancers in African Amerinca women compared to Caucasian women. Current studies include characterizing immune cells in and around breast tumors and the effect of breast feeding on the development of triple negative breast cancer, an aggressive breast cancer that disproportionately affect Black women.

What they’ve learned so far: Drs. Ambrosone and Hong found that tumors from African American women have higher levels of exhausted T cells for all subtypes of breast cancer, and that this is associated with poorer survival. Results from their study on breast feeding has shown that FOXA1–a developmental protein involved in cell differentiation–is supppressed in TNBC and in breast cells of women who do not breast feed after childbirth, suggesting an explanation for the benefit of breast feeding in reducing the risk of breast cancer.

What’s next: In the coming year, the researchers plan to expand the immune cell study with a larger cohort of white women to confirm their initial findings of a prevalence of dysfunctional T-cells in the tumors of Black women compared to white women. With this larger sample size, they will measure a comprehensive panel of proteins in tumors that characterize exhausted immune cells to determine if they are, in fact, more prevalent in tumors from African-American women than Caucasian women and if they are related to poorer survival outcomes in African-American women.

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Professor and Chair
Department of Cancer Prevention and Control
Roswell Park Comprehensive Cancer Center
Buffalo, New York

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BCRF funding allowed us to embark on new avenues of research and explore new hypotheses. Because of BCRF funding, we have made important discoveries regarding the molecular underpinnings of aggressive breast cancer.

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BCRF funding allowed us to embark on new avenues of research and explore new hypotheses. Because of BCRF funding, we have made important discoveries regarding the molecular underpinnings of aggressive breast cancer.

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Understanding the molecular drivers of aggressive breast cancer in Black women and how these are different in white women.

Impact

Black women are 42 percent more likely to die of their breast cancer than white women. Those diagnosed with breast cancer are more likely to be younger than newly diagnosed white women and are two times more likely to be diagnosed with triple-negative breast cancer (TNBC), an aggressive subtype of the disease. Drs. Ambrosone and Hong are investigating several biological and lifestyle factors that may influence the incidence of TNBC in Black women. This work may provide new insights at the population level into why some women develop more aggressive breast tumors so that personalized prevention and treatment can be designed.

Progress Thus Far

The team is studying immune cells that are in and around breast tumors, and how these types of immune cells differ between more aggressive and less aggressive tumor subtypes and between Black women and white women. They showed that some tumors appear to have a strong immune response, but the cells are actually 'exhausted' and dysfunctional. These findings led to a large national study to see if patients with exhausted immune cells, particularly Black women, could benefit from immunotherapy, which can re-invigorate these exhausted cells. Drs. Ambrosone and Hong also found systemic differences in immune profiles in healthy women related to a variant in the DARC gene, which evolved in African populations and stimulates a strong immune response to fight malaria infection.

What’s next

In the coming year, Drs. Ambrosone and Hong will examine whether DARC gene variants are related to breast tumor characteristics, particularly presence of immune cell types, and to survival outcomes. Understanding this may provide a piece of the puzzle as to why Black women tend to have more aggressive breast tumors.

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Understanding the molecular drivers of aggressive breast cancer in Black women and how these are different in white women.

Impact

Black women are 42 percent more likely to die of their breast cancer than white women. Those diagnosed with breast cancer are more likely to be younger than newly diagnosed white women and are two times more likely to be diagnosed with triple-negative breast cancer (TNBC), an aggressive subtype of the disease. Drs. Ambrosone and Hong are investigating several biological and lifestyle factors that may influence the incidence of TNBC in Black women. This work may provide new insights at the population level into why some women develop more aggressive breast tumors so that personalized prevention and treatment can be designed.

Progress Thus Far

The team is studying immune cells that are in and around breast tumors, and how these types of immune cells differ between more aggressive and less aggressive tumor subtypes and between Black women and white women. They showed that some tumors appear to have a strong immune response, but the cells are actually 'exhausted' and dysfunctional. These findings led to a large national study to see if patients with exhausted immune cells, particularly Black women, could benefit from immunotherapy, which can re-invigorate these exhausted cells. Drs. Ambrosone and Hong also found systemic differences in immune profiles in healthy women related to a variant in the DARC gene, which evolved in African populations and stimulates a strong immune response to fight malaria infection.

What’s next

In the coming year, Drs. Ambrosone and Hong will examine whether DARC gene variants are related to breast tumor characteristics, particularly presence of immune cell types, and to survival outcomes. Understanding this may provide a piece of the puzzle as to why Black women tend to have more aggressive breast tumors.

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Learn more about Fabrice André at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Fabrice André | Researcher | Breast Cancer Research Foundation

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Learn more about Fabrice André at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Director of Research, Gustave Roussy Cancer Center
Head, Institut National de la Santé et de la Recherche Médicale Unit U981
Professor, Department of Medical Oncology

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Fabrice André MD, PhD, is an oncologist based at Gustave Roussy Cancer Cancer, Villejuif, France. He is Professor of Medicine at University Paris Saclay. His BCRF research focuses on the characterisation of molecular alterations in metastatic breast cancers. He is leading several prospective trials that aim to show the clinical utility of genomic tests for patients with metastatic breast cancers. He is also leading development of targeted therapies in the same setting. He is the chair of INSERM Unit U981, a research team dedicated to target identification.

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Fabrice André MD, PhD, is an oncologist based at Gustave Roussy Cancer Cancer, Villejuif, France. He is Professor of Medicine at University Paris Saclay. His BCRF research focuses on the characterisation of molecular alterations in metastatic breast cancers. He is leading several prospective trials that aim to show the clinical utility of genomic tests for patients with metastatic breast cancers. He is also leading development of targeted therapies in the same setting. He is the chair of INSERM Unit U981, a research team dedicated to target identification. He is the Editor in Chief of Annals of Oncology.

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Fabrice André MD, PhD, is an oncologist based at Gustave Roussy Cancer Cancer, Villejuif, France. He is Professor of Medicine at University Paris Saclay. His BCRF research focuses on the characterisation of molecular alterations in metastatic breast cancers. He is leading several prospective trials that aim to show the clinical utility of genomic tests for patients with metastatic breast cancers. He is also leading development of targeted therapies in the same setting. He is the chair of INSERM Unit U981, a research team dedicated to target identification. He is the Editor in Chief of Annals of Oncology.

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Research area: Identifying targets for development of novel treatment strategies to prevent resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and improve outcomes for patients.

Impact: Targeted therapies, such as CDK4/6 inhibitors, are standard care with endocrine therapy for patients  with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer. In spite of initial responses, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying genetic markers associated with poor response to this targeted therapy—which could help predict which patients are most likely to benefit from CDK4/6 inhibitors such as alpelisib, other drugs in its class, or novel therapies. These studies could yield new insights into the development of metastases.

Progress Thus Far: Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing. They have identified genomic alterations that were enriched in patients with metastatic breast cancer including the mutation of two genes, KMT2C and CHD4, that are involved in the regulation of gene expression. His team also found that CHD4 mutations predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to CDK4/6 inhibitor, alpelisib (PIQRAY®), which blocks a key protein involved in the progression of breast cancers. His results suggest a role for this protein in response to chemotherapy and therefore, targeted therapy with alpelisib before chemotherapy may benefit some patients.

What’s next: Dr. André and his team are sequencing circulating tumor DNA (ctDNA) from patients before treatment and after tumor progression to identify alterations that may be driving resistance to CDK4/6 directed therapy. Dr. André is also focusing on methods to improve outcomes for patients with hard-to-treat metastatic breast cancer by identifying genomic events that occur before metastasis. His team will perform molecular testing on primary tumors and matched metastases to identify these early events.

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Research area: Identifying targets for development of novel treatment strategies to prevent resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and improve outcomes for patients.

Impact: Targeted therapies, such as CDK4/6 inhibitors, are standard care with endocrine therapy for patients  with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer. In spite of initial responses, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying genetic markers associated with poor response to this targeted therapy—which could help predict which patients are most likely to benefit from CDK4/6 inhibitors such as alpelisib, other drugs in its class, or novel therapies. These studies could yield new insights into the development of metastases.

Progress Thus Far: Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing. They have identified genomic alterations that were enriched in patients with metastatic breast cancer including the mutation of two genes, KMT2C and CHD4, that are involved in the regulation of gene expression. His team also found that CHD4 mutations predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to CDK4/6 inhibitor, alpelisib (PIQRAY®), which blocks a key protein involved in the progression of breast cancers. His results suggest a role for this protein in response to chemotherapy and therefore, targeted therapy with alpelisib before chemotherapy may benefit some patients.

What’s next: Dr. André and his team are sequencing circulating tumor DNA (ctDNA) from patients before treatment and after tumor progression to identify alterations that may be driving resistance to CDK4/6 directed therapy. Dr. André is also focusing on methods to improve outcomes for patients with hard-to-treat metastatic breast cancer by identifying genomic events that occur before metastasis. His team will perform molecular testing on primary tumors and matched metastases to identify these early events.

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Research area: Identifying new targets that mediate resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and that can be used to develop novel treatment strategies to improve outcomes for patients.

Impact: Targeted therapies, such as CDK4/6 inhibitors, are promising treatment options for many breast cancer patients. For patients with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer, CDK4/6 inhibitor combined with endocrine therapy is the standard of care. Although this combination has been transformative, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying mechanisms of resistance which could lead to new targeted treatment combinations to improve outcomes for metastatic breast cancer patients.

Current investigation: Dr. André and his colleagues will focus on the effect of the combination of endocrine therapy and CDK4/6 inhibitors on DNA methylation patterns—chemical modifications that disrupt gene expression—and whether these alterations drive resistance to this therapy.

What he’s learned so far: Dr. André and his colleagues have been focused on the molecular characterization of metastatic breast cancer. Specifically, they have examined biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing and identified genomic alterations that were enriched in patients with metastatic breast cancer. Among these, two genes KMT2C and CHD4 that are involved in the regulation of gene expression, were mutated. His team also found that CHD4 mutations, predict resistance to CDK4/6 inhibitors. These data suggest that KMT2C and CHD2 may be important markers of resistance to endocrine therapy and CDK4/6 inhibitors.

What’s next: Dr. André and his team will analyze the changes in DNA and RNA from 220 breast cancer samples before and after combined treatment with endocrine therapy and CDK4/6 inhibitors. Their analysis will reveal DNA methylation patterns associated with KMT2C and CHD4 mutations that have occurred with treatment and will help them evaluate the role of KMT2C and CHD4 in resistance to combined endocrine and anti-CDK4/6 therapy.

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Research area: Identifying new targets that mediate resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and that can be used to develop novel treatment strategies to improve outcomes for patients.

Impact: Targeted therapies, such as CDK4/6 inhibitors, are promising treatment options for many breast cancer patients. For patients with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer, CDK4/6 inhibitor combined with endocrine therapy is the standard of care. Although this combination has been transformative, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying mechanisms of resistance which could lead to new targeted treatment combinations to improve outcomes for metastatic breast cancer patients.

Current investigation: Dr. André and his colleagues will focus on the effect of the combination of endocrine therapy and CDK4/6 inhibitors on DNA methylation patterns—chemical modifications that disrupt gene expression—and whether these alterations drive resistance to this therapy.

What he’s learned so far: Dr. André and his colleagues have been focused on the molecular characterization of metastatic breast cancer. Specifically, they have examined biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing and identified genomic alterations that were enriched in patients with metastatic breast cancer. Among these, two genes KMT2C and CHD4 that are involved in the regulation of gene expression, were mutated. His team also found that CHD4 mutations, predict resistance to CDK4/6 inhibitors. These data suggest that KMT2C and CHD2 may be important markers of resistance to endocrine therapy and CDK4/6 inhibitors.

What’s next: Dr. André and his team will analyze the changes in DNA and RNA from 220 breast cancer samples before and after combined treatment with endocrine therapy and CDK4/6 inhibitors. Their analysis will reveal DNA methylation patterns associated with KMT2C and CHD4 mutations that have occurred with treatment and will help them evaluate the role of KMT2C and CHD4 in resistance to combined endocrine and anti-CDK4/6 therapy.

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Director of Research, Gustave Roussy Cancer Center
Head, Institut National de la Santé et de la Recherche Médicale Unit U981
Professor, Department of Medical Oncology

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Seeking targets that may quickly identify patients with hard-to-treat breast cancer so that more accurate treatment decisions can be made in real time.

Impact

Targeted therapies, such as CDK4/6 or P13K inhibitors, in combination with endocrine therapy are standard of care for treating metastatic hormone receptor (HR)-positive/HER2-negative breast cancer patients. In spite of initial responses, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying genetic markers associated with poor response to targeted therapies with particular focus on response to the P13K inhibitor alpelisib ((PIQRAY®). His research may uncover ways to predict which patients are most likely to benefit from alpelisib, other drugs in its class, or other novel therapies so that treatment decisions can be made more nimbly and accurately. His results will also yield new insights into the development of metastases and improve outcomes for these patients.

Progress Thus Far

Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast tumors by whole exome sequencing. In his work, they uncovered genomic alterations in several important genes including CHD4, which his team found to predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to P13K inhibitor, alpelisib (PIQRAY®), which blocks a key protein (PIK3CA) involved in the progression of breast cancers. HR-positive/HER2-negative tumors that have PIK3CA gene mutations benefited from treatment with alpelisib. Using liquid biopsy techniques, his team found that PIK3CA mutations in the blood of patients with metastatic breast cancer was a predictor of worse outcome compared to those without PIK3CA mutations His results suggest a role for this protein in response to targeted therapy.

What’s next

The team is testing the utility of liquid biopsy to identify non-responding patients early in the course of treatment. They will continue to sequence biopsy samples from patients before treatment and after tumor progression to identify alterations that may be driving therapy resistance. By identifying genomic events that occur before metastasis, treatment decisions could then be adjusted in real time to ultimately prevent disease progression and improve outcomes for patients with hard-to-treat metastatic breast cancer.

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Seeking targets that may quickly identify patients with hard-to-treat breast cancer so that more accurate treatment decisions can be made in real time.

Impact

Targeted therapies, such as CDK4/6 or P13K inhibitors, in combination with endocrine therapy are standard of care for treating metastatic hormone receptor (HR)-positive/HER2-negative breast cancer patients. In spite of initial responses, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying genetic markers associated with poor response to targeted therapies with particular focus on response to the P13K inhibitor alpelisib ((PIQRAY®). His research may uncover ways to predict which patients are most likely to benefit from alpelisib, other drugs in its class, or other novel therapies so that treatment decisions can be made more nimbly and accurately. His results will also yield new insights into the development of metastases and improve outcomes for these patients.

Progress Thus Far

Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast tumors by whole exome sequencing. In his work, they uncovered genomic alterations in several important genes including CHD4, which his team found to predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to P13K inhibitor, alpelisib (PIQRAY®), which blocks a key protein (PIK3CA) involved in the progression of breast cancers. HR-positive/HER2-negative tumors that have PIK3CA gene mutations benefited from treatment with alpelisib. Using liquid biopsy techniques, his team found that PIK3CA mutations in the blood of patients with metastatic breast cancer was a predictor of worse outcome compared to those without PIK3CA mutations His results suggest a role for this protein in response to targeted therapy.

What’s next

The team is testing the utility of liquid biopsy to identify non-responding patients early in the course of treatment. They will continue to sequence biopsy samples from patients before treatment and after tumor progression to identify alterations that may be driving therapy resistance. By identifying genomic events that occur before metastasis, treatment decisions could then be adjusted in real time to ultimately prevent disease progression and improve outcomes for patients with hard-to-treat metastatic breast cancer.

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Learn more about Michael Andreeff at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Michael Andreeff | Researcher | Breast Cancer Research Foundation

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Learn more about Michael Andreeff at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Paul and Mary Haas Chair in Genetics
Chief, Section of Molecular Hematology and Therapy
Professor of Medicine, Department of Leukemia
Professor of Medicine, Department of Stem Cell Transplantation

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The University of Texas MD Anderson Cancer Center

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Michael Andreeff received his MD and PhD from the University of Heidelberg, Germany, and additional training at Memorial Sloan Kettering Cancer Center. He has been a pioneer in flow cytometry since 1971, when he established the first flow cytometry laboratory at the University of Heidelberg and organized the first European flow cytometry conference. In 1977 he joined MSKCC, became head of the Leukemia Cell Biology and Hematopathology flow cytometry laboratory, and organized the first Clinical Cytometry Conference in 1986.

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Michael Andreeff received his MD and PhD from the University of Heidelberg, Germany, and additional training at Memorial Sloan Kettering Cancer Center. He has been a pioneer in flow cytometry since 1971, when he established the first flow cytometry laboratory at the University of Heidelberg and organized the first European flow cytometry conference. In 1977 he joined MSKCC, became head of the Leukemia Cell Biology and Hematopathology flow cytometry laboratory, and organized the first Clinical Cytometry Conference in 1986. Since 1990 he has been Professor of Medicine at MD Anderson Cancer Center where he holds the Paul and Mary Haas Chair in Genetics. He has published over 450 peer-reviewed papers, 5 books and 75 book chapters.

Dr. Andreeff’s group has worked extensively on drug resistance in hematopoietic malignancies and breast cancer and  developed or co-developed several new therapeutic agents including the novel triterpenoids CDDO and CDDO-Me and  Bcl-2- , XIAP- , surviving-, MEK-   and HDM2- inhibitors. Over the last decade, his group has made major contributions to the understanding of micro-environment-mediated drug resistance and developed strategies to exploit the underlying mechanisms for the treatment of  hematopoietic and epithelial malignancies. His group reported the role of bone marrow-derived multipotent mesenchymal stromal cells (MSC) In tumor stroma formation and developed therapeutic strategies based on this discovery.

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Michael Andreeff received his MD and PhD from the University of Heidelberg, Germany, and additional training at Memorial Sloan Kettering Cancer Center. He has been a pioneer in flow cytometry since 1971, when he established the first flow cytometry laboratory at the University of Heidelberg and organized the first European flow cytometry conference. In 1977 he joined MSKCC, became head of the Leukemia Cell Biology and Hematopathology flow cytometry laboratory, and organized the first Clinical Cytometry Conference in 1986. Since 1990 he has been Professor of Medicine at MD Anderson Cancer Center where he holds the Paul and Mary Haas Chair in Genetics. He has published over 450 peer-reviewed papers, 5 books and 75 book chapters.

Dr. Andreeff’s group has worked extensively on drug resistance in hematopoietic malignancies and breast cancer and developed or co-developed several new therapeutic agents including the novel triterpenoids CDDO and CDDO-Me and Bcl-2- , XIAP- , surviving-, MEK- and HDM2- inhibitors. Over the last decade, his group has made major contributions to the understanding of micro-environment-mediated drug resistance and developed strategies to exploit the underlying mechanisms for the treatment of hematopoietic and epithelial malignancies. His group reported the role of bone marrow-derived multipotent mesenchymal stromal cells (MSC) In tumor stroma formation and developed therapeutic strategies based on this discovery.

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Goal: To improve treatments for advanced triple negative breast cancer (TNBC).

Impact: Dr. Andreeff is studying metabolic pathways that are activated in breast cancer stem cells (BCSCs). These cells are thought to drive aggressive tumor behavior and are resistant to chemotherapy. His work may inform the development of novel therapeutic strategies to improve outcomes for patients with TNBC.

What’s next: He and his team discovered GD2, a target on BCSCs and TNBC. They aim to target BCSCs and remaining tumor cells by combining an anti-GD2 antibody (dinutuximab) in combination with immune checkpoint therapy to enhance anti-tumor immune cell activity.

TNBC is difficult to treat due to a lack of targeted therapies and resistance of TNBC tumors to several drugs. Dr. Andreeff has identified a new target on breast cancer stem-like cells (BCSCs) that are resistant to chemotherapy and are capable of metastasizing (spreading the tumor to other parts of the body). The target, called GD2, is highly expressed in TNBC. He and his team are now testing a drug called dinutuximab that targets GD2 in combination with immune checkpoint therapy.

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Goal: To improve treatments for advanced triple negative breast cancer (TNBC).

Impact: Dr. Andreeff is studying metabolic pathways that are activated in breast cancer stem cells (BCSCs). These cells are thought to drive aggressive tumor behavior and are resistant to chemotherapy. His work may inform the development of novel therapeutic strategies to improve outcomes for patients with TNBC.

What’s next: He and his team discovered GD2, a target on BCSCs and TNBC. They aim to target BCSCs and remaining tumor cells by combining an anti-GD2 antibody (dinutuximab) in combination with immune checkpoint therapy to enhance anti-tumor immune cell activity.

TNBC is difficult to treat due to a lack of targeted therapies and resistance of TNBC tumors to several drugs. Dr. Andreeff has identified a new target on breast cancer stem-like cells (BCSCs) that are resistant to chemotherapy and are capable of metastasizing (spreading the tumor to other parts of the body). The target, called GD2, is highly expressed in TNBC. He and his team are now testing a drug called dinutuximab that targets GD2 in combination with immune checkpoint therapy.

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Research area: Identifying ways to target breast cancer stem cells (BCSCs) in patients with triple negative breast cancer (TNBC).

Impact: While targeted therapies are available for several subtypes of breast cancer, there are few approved for TNBC, which is aggressive and difficult to treat. Chemotherapy is standard-of-care, but many patients become resistant to this treatment. Dr. Andreeff is investigating ways to target BCSCs, which are believed to drive aggressive tumor behavior. His findings could lead to the development of new targeted therapies for TNBC.

Current investigation: He and his team are focused on GD2, a new target they identified on BCSCs that is highly expressed in TNBC. They have been developing strategies to eliminate these cells using an immunotherapeutic antibody that is FDA-approved for treating neuroblastoma.

What he’s learned so far: Because of their rapid growth and high energy needs, tumors are highly dependent on glucose metabolism. When glucose is in short supply—as often happens as tumors grow—it causes “metabolic stress” within the tumor. Dr. Andreeff’s team has shown that metabolic stress caused by nutrient deprivation (low glucose) increases levels of GD2 and induces cancer stem cell-like characteristics in TNBCs. By blocking the cells’ update of glutamine—an essential amino acid in glucose metabolism—they were able to reverse the effect of GD2 and increase the effectiveness of chemotherapy.

What’s next: Dr. Andreeff and his colleagues are testing an anti-GD2 antibody (dinutuximab) in combination with immunotherapy checkpoint inhibitors to target BCSCs. They will couple this to laboratory experiments to determine the role of glutamine on GD2 expression in BCSCs and explore targeting this pathway as a novel therapeutic strategy.

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Research area: Identifying ways to target breast cancer stem cells (BCSCs) in patients with triple negative breast cancer (TNBC).

Impact: While targeted therapies are available for several subtypes of breast cancer, there are few approved for TNBC, which is aggressive and difficult to treat. Chemotherapy is standard-of-care, but many patients become resistant to this treatment. Dr. Andreeff is investigating ways to target BCSCs, which are believed to drive aggressive tumor behavior. His findings could lead to the development of new targeted therapies for TNBC.

Current investigation: He and his team are focused on GD2, a new target they identified on BCSCs that is highly expressed in TNBC. They have been developing strategies to eliminate these cells using an immunotherapeutic antibody that is FDA-approved for treating neuroblastoma.

What he’s learned so far: Because of their rapid growth and high energy needs, tumors are highly dependent on glucose metabolism. When glucose is in short supply—as often happens as tumors grow—it causes “metabolic stress” within the tumor. Dr. Andreeff’s team has shown that metabolic stress caused by nutrient deprivation (low glucose) increases levels of GD2 and induces cancer stem cell-like characteristics in TNBCs. By blocking the cells’ update of glutamine—an essential amino acid in glucose metabolism—they were able to reverse the effect of GD2 and increase the effectiveness of chemotherapy.

What’s next: Dr. Andreeff and his colleagues are testing an anti-GD2 antibody (dinutuximab) in combination with immunotherapy checkpoint inhibitors to target BCSCs. They will couple this to laboratory experiments to determine the role of glutamine on GD2 expression in BCSCs and explore targeting this pathway as a novel therapeutic strategy.

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Paul and Mary Haas Chair in Genetics
Chief, Section of Molecular Hematology and Therapy
Professor of Medicine, Department of Leukemia
Professor of Medicine, Department of Stem Cell Transplantation

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Improving treatments for advanced triple-negative breast cancer.

Impact

While targeted therapies are available for several subtypes of breast cancer, there are few approved for triple-negative breast cancer (TNBC), which is aggressive and difficult to treat. In search of new therapeutic options for TNBC, Dr. Andreeff and his team identified a molecule called GD2 that appears to be specifically overproduced by breast cancer stem cells—a population that may drive tumor growth and therapeutic resistance. The team is exploring how GD2 functions in TNBC and the potential uses of GD2-targeting therapies.

Progress Thus Far

Thus far, the team unveiled several interesting roles for GD2 in TNBC progression. They discovered that TNBC tumor growth can be inhibited by depriving tumors of GD2. In addition, they detected high levels of GD2 in approximately 60 percent of primary TNBC tumors and found it to be associated with poor overall survival. More recently, they uncovered that a tumor’s unique metabolic state may contribute to the increased production of GD2, and that GD2 blocks immune cells from attacking tumors. In laboratory studies, they found a potentially successful combination approach that targets GD2 while activating an anti-tumor immune response.

What's next

In this upcoming year, Dr. Andreeff and his team will continue to explore potential therapeutic strategies for targeting GD2, using an FDA-approved antibody therapy that is already approved for the treatment of neuroblastoma. They will also work to enhance the activity of immune cells that are typically suppressed by GD2, focusing on a population of immune cells known as natural killer cells.

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Improving treatments for advanced triple-negative breast cancer.

Impact

While targeted therapies are available for several subtypes of breast cancer, there are few approved for triple-negative breast cancer (TNBC), which is aggressive and difficult to treat. In search of new therapeutic options for TNBC, Dr. Andreeff and his team identified a molecule called GD2 that appears to be specifically overproduced by breast cancer stem cells—a population that may drive tumor growth and therapeutic resistance. The team is exploring how GD2 functions in TNBC and the potential uses of GD2-targeting therapies.

Progress Thus Far

Thus far, the team unveiled several interesting roles for GD2 in TNBC progression. They discovered that TNBC tumor growth can be inhibited by depriving tumors of GD2. In addition, they detected high levels of GD2 in approximately 60 percent of primary TNBC tumors and found it to be associated with poor overall survival. More recently, they uncovered that a tumor’s unique metabolic state may contribute to the increased production of GD2, and that GD2 blocks immune cells from attacking tumors. In laboratory studies, they found a potentially successful combination approach that targets GD2 while activating an anti-tumor immune response.

What's next

In this upcoming year, Dr. Andreeff and his team will continue to explore potential therapeutic strategies for targeting GD2, using an FDA-approved antibody therapy that is already approved for the treatment of neuroblastoma. They will also work to enhance the activity of immune cells that are typically suppressed by GD2, focusing on a population of immune cells known as natural killer cells.

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Learn more about Joaquin Arribas at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Joaquin Arribas | Researcher | Breast Cancer Research Foundation

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Learn more about Joaquin Arribas at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Associate Professor, Department of Medicine and Life Sciences,
Universitat Pompeu Fabra
Research Director, Consortium Mar Health Park of Barcelona and Hospital del Mar Institute of Medical Research
Director, Preclinical Research Program

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Dr. Joaquin Arribas is the Director of Preclinical Research Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain, where he leads a group focused on the study of growth factors, growth factor receptors, and the proteases involved in remodeling the cell surface. He is a member of the Editorial Board of the Journal of Biological Chemistry, Translational Oncology, and CDB Protein Systems.

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Dr. Joaquin Arribas is the Director of Preclinical Research Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain, where he leads a group focused on the study of growth factors, growth factor receptors, and the proteases involved in remodeling the cell surface. He is a member of the Editorial Board of the Journal of Biological Chemistry, Translational Oncology, and CDB Protein Systems.

Dr. Arribas is member of the Spanish and American Societies of Biochemistry and Molecular Biology and President of the Committee for the Evaluation of Cancer Research project at the Institute of Health Carlos III, a major public funding agency in Spain.

Dr. Arribas completed his undergraduate studies in biochemistry at the University of Madrid, where he subsequently worked on the regulation of the catalytic activities of the proteasome and received a PhD in biology in 1991. Sponsored by a fellowship from the Spanish Ministry of Education and Science, he joined Memorial Sloan Kettering Cancer Center in New York as a postdoctoral fellow to work with Dr. Joan Massague (1992-1996) on the proteolytic processing of transmembrane growth factors. In 1997, he joined the Oncology Department at Hospital Vall d'Hebron as a staff scientist and was promoted to lead the oncology research department in 2001. Dr. Arribas’s research has been recognized by the European Molecular Biology Organization (EMBO), which honored him with a Young Investigator Program (YIP) Award. Also, Dr. Arribas received the Beckman Coulter Award conferred on the Best Young Spanish Investigator in Biochemistry and Molecular Biology.

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Dr. Joaquin Arribas is the Director of Preclinical Research Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain, where he leads a group focused on the study of growth factors, growth factor receptors, and the proteases involved in remodeling the cell surface. He is a member of the Editorial Board of the Journal of Biological Chemistry, Translational Oncology, and CDB Protein Systems.

Dr. Arribas is member of the Spanish and American Societies of Biochemistry and Molecular Biology and President of the Committee for the Evaluation of Cancer Research project at the Institute of Health Carlos III, a major public funding agency in Spain.

Dr. Arribas completed his undergraduate studies in biochemistry at the University of Madrid, where he subsequently worked on the regulation of the catalytic activities of the proteasome and received a PhD in biology in 1991. Sponsored by a fellowship from the Spanish Ministry of Education and Science, he joined Memorial Sloan Kettering Cancer Center in New York as a postdoctoral fellow to work with Dr. Joan Massague (1992-1996) on the proteolytic processing of transmembrane growth factors. In 1997, he joined the Oncology Department at Hospital Vall d'Hebron as a staff scientist and was promoted to lead the oncology research department in 2001. Dr. Arribas’s research has been recognized by the European Molecular Biology Organization (EMBO), which honored him with a Young Investigator Program (YIP) Award. Also, Dr. Arribas received the Beckman Coulter Award conferred on the Best Young Spanish Investigator in Biochemistry and Molecular Biology.

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Goal: To identify new targets that will improve response to HER2-targeted therapies.

Impact: Dr. Arribas is testing novel therapies developed by his team to treat a subtype of HER2-positive tumors that tend to be particularly aggressive and resistant to treatment. His work may lead to a new combination treatment to improve the effectiveness of HER2-targeted therapies.

What’s next: He and his team will identify methods of resistance to this drug in order to find novel therapeutic approaches to overcome them.

While HER2-directed therapies such as trastuzumab have been effective in treating many HER2-positive breast cancers, not all tumors respond to these drugs. Others become resistant during the course of therapy. Dr. Arribas has developed novel therapies that induce an immune reaction against tumor cells that may benefit patients who have a particularly aggressive and treatment resistant type of HER2-positive breast cancer.

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Goal: To identify new targets that will improve response to HER2-targeted therapies.

Impact: Dr. Arribas is testing novel therapies developed by his team to treat a subtype of HER2-positive tumors that tend to be particularly aggressive and resistant to treatment. His work may lead to a new combination treatment to improve the effectiveness of HER2-targeted therapies.

What’s next: He and his team will identify methods of resistance to this drug in order to find novel therapeutic approaches to overcome them.

While HER2-directed therapies such as trastuzumab have been effective in treating many HER2-positive breast cancers, not all tumors respond to these drugs. Others become resistant during the course of therapy. Dr. Arribas has developed novel therapies that induce an immune reaction against tumor cells that may benefit patients who have a particularly aggressive and treatment resistant type of HER2-positive breast cancer.

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Research area: Developing combination therapies to improve clinical outcomes in patients with HER2-positive breast cancer.

Impact: HER2-positive breast cancer accounts for approximately 20 to 30 percent of all breast cancer cases. HER2-targeting treatments are effective in treating many of these tumors, but some tumors do not respond to them, while others become resistant during therapy. Dr. Arribas has developed novel therapies that target a type of HER2-positive tumor that is characterized by the presence of a truncated from of HER2 called p95HER2. This form of HER2 is particularly active and promotes malignant transformation of the cancer cell. His work could pave the way for new combination treatments for p95HER2-positive tumors.

Current research: Dr. Arribas and his colleagues are conducting laboratory studies to identify and fully test novel approaches to improve outcomes in patients with an aggressive type of HER2-positive breast cancer.

What he’s learned so far: Dr. Arribas and his colleagues have shown that a subgroup of HER2-postiive tumors express a truncated form of HER2, p95HER2, in addition to a full-length HER2 protein. This truncated form of HER2 is completely absent in normal tissues. Moreover, the tumors that express p95HER2 are particularly aggressive. They have recently developed novel therapies to target p95HER2- by inducing an immune reaction against these tumor cells. Recent studies have shown that tumor relapses and side effects of anti-tumor therapies are due, at least in part, to the accumulation of damaged cells that undergo a resting state known as cellular senescence. Therefore, Dr. Arribas and his team have also developed a model that will allow them to study tumor cell senescence to identify ways to effectively eliminate these dormant cancer cells.

What’s next: Dr. Arribas and his colleagues will continue to develop novel therapies to direct immune cells against the p95HER2 subtype of tumors in an effective and safe manner. To anticipate the clinical needs associated with the use of these novel therapies, they will also characterize the mechanisms of resistance to identify specific vulnerabilities of these resistant cells that may be targeted by new combination strategies. Ultimately, they hope to be able to eliminate senescent cells to improve patient response to treatment.

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Research area: Developing combination therapies to improve clinical outcomes in patients with HER2-positive breast cancer.

Impact: HER2-positive breast cancer accounts for approximately 20 to 30 percent of all breast cancer cases. HER2-targeting treatments are effective in treating many of these tumors, but some tumors do not respond to them, while others become resistant during therapy. Dr. Arribas has developed novel therapies that target a type of HER2-positive tumor that is characterized by the presence of a truncated from of HER2 called p95HER2. This form of HER2 is particularly active and promotes malignant transformation of the cancer cell. His work could pave the way for new combination treatments for p95HER2-positive tumors.

Current research: Dr. Arribas and his colleagues are conducting laboratory studies to identify and fully test novel approaches to improve outcomes in patients with an aggressive type of HER2-positive breast cancer.

What he’s learned so far: Dr. Arribas and his colleagues have shown that a subgroup of HER2-postiive tumors express a truncated form of HER2, p95HER2, in addition to a full-length HER2 protein. This truncated form of HER2 is completely absent in normal tissues. Moreover, the tumors that express p95HER2 are particularly aggressive. They have recently developed novel therapies to target p95HER2- by inducing an immune reaction against these tumor cells. Recent studies have shown that tumor relapses and side effects of anti-tumor therapies are due, at least in part, to the accumulation of damaged cells that undergo a resting state known as cellular senescence. Therefore, Dr. Arribas and his team have also developed a model that will allow them to study tumor cell senescence to identify ways to effectively eliminate these dormant cancer cells.

What’s next: Dr. Arribas and his colleagues will continue to develop novel therapies to direct immune cells against the p95HER2 subtype of tumors in an effective and safe manner. To anticipate the clinical needs associated with the use of these novel therapies, they will also characterize the mechanisms of resistance to identify specific vulnerabilities of these resistant cells that may be targeted by new combination strategies. Ultimately, they hope to be able to eliminate senescent cells to improve patient response to treatment.

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Associate Professor, Department of Medicine and Life Sciences, 
Universitat Pompeu Fabra 
Research Director, Consortium Mar Health Park of Barcelona and Hospital del Mar Institute of Medical Research 
Director, Preclinical Research Program  

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Developing novel therapies that utilize the power of the immune system to treat breast cancer.

Impact

Normal cells respond to damage by halting cell division, putting the cells in a state of cellular senescence. Similarly, malignant cells will become senescent in response to some therapies. While senescent tumor cells no longer proliferate, they remain molecularly active and produce factors that promote aggressiveness in neighboring tumor cells. Dr. Arribas’ team is focused on developing novel strategies that redirect the immune system against senescent cells, thereby eradicating them and increasing the efficacy of breast cancer therapies.

Progress thus far

Dr. Arribas and his colleagues developed experimental models that helped to establish that cellular senescence can exert either anti- or pro-tumorigenic effects depending on the stage of the tumor and the immune cells present in the immediate tumor environment. In addition,  specifically depleting senescent cells has an anti-tumor effect. Preliminary studies indicate that senescent cells promote the anti-tumor immune response at early stages of tumor formation while inhibiting it at later stages. Dr. Arribas and his group have also identified candidate cell surface molecules (PD-L2 and LRRC15) that are overexpressed in senescent cells.

What’s next

Dr. Arribas and his team will continue to identify other cell surface molecules (in addition to PD-L2 and LRRC15) as candidates for the development of redirected immune cells. The molecule LRRC15 will be also used to develop antibodies. If successful, this novel strategy of targeting senescent cells with redirected immune constructs will help to expand the number of anti-tumor tools in our arsenal for treating breast cancer.

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Developing novel therapies that utilize the power of the immune system to treat breast cancer.

Impact

Normal cells respond to damage by halting cell division, putting the cells in a state of cellular senescence. Similarly, malignant cells will become senescent in response to some therapies. While senescent tumor cells no longer proliferate, they remain molecularly active and produce factors that promote aggressiveness in neighboring tumor cells. Dr. Arribas’ team is focused on developing novel strategies that redirect the immune system against senescent cells, thereby eradicating them and increasing the efficacy of breast cancer therapies.

Progress thus far

Dr. Arribas and his colleagues developed experimental models that helped to establish that cellular senescence can exert either anti- or pro-tumorigenic effects depending on the stage of the tumor and the immune cells present in the immediate tumor environment. In addition,  specifically depleting senescent cells has an anti-tumor effect. Preliminary studies indicate that senescent cells promote the anti-tumor immune response at early stages of tumor formation while inhibiting it at later stages. Dr. Arribas and his group have also identified candidate cell surface molecules (PD-L2 and LRRC15) that are overexpressed in senescent cells.

What’s next

Dr. Arribas and his team will continue to identify other cell surface molecules (in addition to PD-L2 and LRRC15) as candidates for the development of redirected immune cells. The molecule LRRC15 will be also used to develop antibodies. If successful, this novel strategy of targeting senescent cells with redirected immune constructs will help to expand the number of anti-tumor tools in our arsenal for treating breast cancer.

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Learn more about Alan Ashworth at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Alan Ashworth | Researcher | Breast Cancer Research Foundation

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Learn more about Alan Ashworth at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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President, Helen Diller Family Comprehensive Cancer Center
Senior Vice President for Cancer Services, UCSF Health
Professor of Medicine, Division of Hematology/Oncology

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Alan Ashworth, PhD, FR, is President of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, a role he began in January 2015.  He was previously Chief Executive of the Institute of Cancer Research (ICR) in London, United Kingdom.
In 1999 he was appointed the first Director of the Breakthrough Breast Cancer Research Centre where he was also Professor of Molecular Biology and leader of the Gene Function team.  Professor Ashworth’s Directorship ended in January 2011 when was appointed Chief Executive of the ICR.

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Alan Ashworth, PhD, FR, is President of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, a role he began in January 2015.  He was previously Chief Executive of the Institute of Cancer Research (ICR) in London, United Kingdom.

In 1999 he was appointed the first Director of the Breakthrough Breast Cancer Research Centre where he was also Professor of Molecular Biology and leader of the Gene Function team.  Professor Ashworth’s Directorship ended in January 2011 when was appointed Chief Executive of the ICR.

A translational biologist and laboratory researcher, Dr. Ashworth’s research focuses on understanding breast cancer genetics and applying what he learns to change the way patients are treated. He was a key part of the team that identified the BRCA2 breast cancer susceptibility gene, which is linked to an increased risk of some types of cancer.  Ten years later, Dr. Ashworth found a way to kill off BRCA1- and 2-related tumor cells by treating them with PARP inhibitors, which amplifies the damage caused by the broken DNA repair machinery in those cells.  This exemplifies the genetic principle of synthetic lethality in cancer therapy.

Dr. Ashworth is an elected member of EMBO and the Academy of Medical Sciences and a Fellow of the Royal Society. He has been the recipient of a number of scientific prizes and awards including The European Society of Medical Oncology Lifetime Achievement Award, the David T. Workman Memorial Award of the Samuel Waxman Cancer Research Foundation and the Meyenburg Foundation’s Cancer Research Award and was the inaugural winner of the 2013 Basser Global Prize. He has also recently been selected as the recipient of the 2015 Genetics Society Medal.

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Alan Ashworth, PhD, FR, is President of the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, a role he began in January 2015.  He was previously Chief Executive of the Institute of Cancer Research (ICR) in London, United Kingdom.

In 1999 he was appointed the first Director of the Breakthrough Breast Cancer Research Centre where he was also Professor of Molecular Biology and leader of the Gene Function team.  Professor Ashworth’s Directorship ended in January 2011 when was appointed Chief Executive of the ICR.

A translational biologist and laboratory researcher, Dr. Ashworth’s research focuses on understanding breast cancer genetics and applying what he learns to change the way patients are treated. He was a key part of the team that identified the BRCA2 breast cancer susceptibility gene, which is linked to an increased risk of some types of cancer.  Ten years later, Dr. Ashworth found a way to kill off BRCA1- and 2-related tumor cells by treating them with PARP inhibitors, which amplifies the damage caused by the broken DNA repair machinery in those cells.  This exemplifies the genetic principle of synthetic lethality in cancer therapy.

Dr. Ashworth is an elected member of EMBO and the Academy of Medical Sciences and a Fellow of the Royal Society. He has been the recipient of a number of scientific prizes and awards including The European Society of Medical Oncology Lifetime Achievement Award, the David T. Workman Memorial Award of the Samuel Waxman Cancer Research Foundation and the Meyenburg Foundation’s Cancer Research Award and was the inaugural winner of the 2013 Basser Global Prize. He has also recently been selected as the recipient of the 2015 Genetics Society Medal.

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Research Area: Identifying new therapeutic targets for aggressive forms of breast cancer.

Impact: Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis. Although TNBC patients benefit from standard chemotherapy, and some fare well with new immunotherapies, overall, they face high recurrence rates and are more likely to develop chemoresistance. There is therefore an urgent need to develop new targeted therapies for these patients.

Progress Thus Far: Dr. Ashworth and his team have identified a protein called xCT as a potentially promising therapeutic target for TNBC. xCT is a protein that serves as a molecular transporter; It sits within the outer membranes of cells, funneling specific molecules into the cell and expelling others. Tumor cells can use it to eject chemotherapies and take in nutrients. While it is dispensable for the function of healthy cells, loss of xCT function is lethal to tumor cells, making it an attractive therapeutic target. Importantly, xCT is present in approximately half of TNBC tumors and high levels are associated with worse outcomes for patients.

What’s next: Dr. Ashworth’s team will pursue multiple strategies to generate xCT therapies, including developing therapeutic antibodies and testing thousands of small molecular compounds that might block xCT’s activity. Promising drugs will be assessed in the laboratory with the ultimate goal of being tested in clinical trials.

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Research Area: Identifying new therapeutic targets for aggressive forms of breast cancer.

Impact: Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis. Although TNBC patients benefit from standard chemotherapy, and some fare well with new immunotherapies, overall, they face high recurrence rates and are more likely to develop chemoresistance. There is therefore an urgent need to develop new targeted therapies for these patients.

Progress Thus Far: Dr. Ashworth and his team have identified a protein called xCT as a potentially promising therapeutic target for TNBC. xCT is a protein that serves as a molecular transporter; It sits within the outer membranes of cells, funneling specific molecules into the cell and expelling others. Tumor cells can use it to eject chemotherapies and take in nutrients. While it is dispensable for the function of healthy cells, loss of xCT function is lethal to tumor cells, making it an attractive therapeutic target. Importantly, xCT is present in approximately half of TNBC tumors and high levels are associated with worse outcomes for patients.

What’s next: Dr. Ashworth’s team will pursue multiple strategies to generate xCT therapies, including developing therapeutic antibodies and testing thousands of small molecular compounds that might block xCT’s activity. Promising drugs will be assessed in the laboratory with the ultimate goal of being tested in clinical trials.

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Research area: Understanding how various genes affect tumor cell behavior and to identify targets to reduce resistance to anti-cancer therapies.

Impact: While many advances have been made in the treatment of breast cancer, not all patients respond to available therapies. This is partly due to the genetic makeup of the tumor. Dr. Ashworth aims to identify genetic vulnerabilities in breast cancer that can inform novel therapeutic strategies for patients.

Current investigation: He and his team are investigating how specific genes promote resistance to PARP inhibitors in BRCA-mutated breast cancer. In addition, they are studying genes that are essential for cancer cell survival when p53, a tumor suppressor, is mutated. This occurs in approximately 75 percent of triple negative breast cancers and the goal is to identify new vulnerabilities in the cell that could be targeted in these cancers.

What he’s accomplished so far: Dr. Ashworth recently completed a screen for genes that cause BRCA-mutated breast cancer cells to become resistant to the PARP inhibitor olaparib and identified several interesting candidates. He and his team have built CRISPR libraries targeting proteins that are important for the survival of cancer cells with common p53 mutations.

What’s next: In the coming year, Dr. Ashworth will work to establish how the expression of the target genes they have identified promotes resistance to olaparib. He and his team will also analyze DNA and RNA samples collected from patients treated with olaparib and an immune checkpoint inhibitor to look for biomarkers that correspond with response. Dr. Ashworth has also begun initial studies to look for dependencies associated with specific p53 mutations.

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Research area: Understanding how various genes affect tumor cell behavior and to identify targets to reduce resistance to anti-cancer therapies.

Impact: While many advances have been made in the treatment of breast cancer, not all patients respond to available therapies. This is partly due to the genetic makeup of the tumor. Dr. Ashworth aims to identify genetic vulnerabilities in breast cancer that can inform novel therapeutic strategies for patients.

Current investigation: He and his team are investigating how specific genes promote resistance to PARP inhibitors in BRCA-mutated breast cancer. In addition, they are studying genes that are essential for cancer cell survival when p53, a tumor suppressor, is mutated. This occurs in approximately 75 percent of triple negative breast cancers and the goal is to identify new vulnerabilities in the cell that could be targeted in these cancers.

What he’s accomplished so far: Dr. Ashworth recently completed a screen for genes that cause BRCA-mutated breast cancer cells to become resistant to the PARP inhibitor olaparib and identified several interesting candidates. He and his team have built CRISPR libraries targeting proteins that are important for the survival of cancer cells with common p53 mutations.

What’s next: In the coming year, Dr. Ashworth will work to establish how the expression of the target genes they have identified promotes resistance to olaparib. He and his team will also analyze DNA and RNA samples collected from patients treated with olaparib and an immune checkpoint inhibitor to look for biomarkers that correspond with response. Dr. Ashworth has also begun initial studies to look for dependencies associated with specific p53 mutations.

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President, Helen Diller Family Comprehensive Cancer Center
Senior Vice President for Cancer Services, UCSF Health
Professor of Medicine, Division of Hematology/Oncology

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Identifying new therapeutic targets for aggressive forms of breast cancer.

Impact

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis. Although TNBC patients benefit from standard chemotherapy, and some fare well with new immunotherapies, overall, they face high recurrence rates and are more likely to develop chemoresistance. There is therefore an urgent need to develop new targeted therapies for these patients.

Progress Thus Far

Dr. Ashworth and his team identified a protein called xCT as a potentially promising therapeutic target for TNBC. This protein serves as a molecular transporter; it sits within the outer membranes of cells, funneling specific molecules into the cell and expelling others. Tumor cells can use it to eject chemotherapies and take in nutrients. While it is dispensable for the function of healthy cells, loss of xCT function is lethal to tumor cells, making it an attractive therapeutic target. Importantly, xCT is present in approximately half of TNBC tumors and high levels are associated with worse outcomes for patients. Over the past year the team pursued two complementary strategies that will help them identify promising xCT therapies. They engineered both a nano sensor and a chemical probe, which will help signal if a drug they are testing is effectively blocking xCT.

What’s next

Dr. Ashworth’s team will pursue multiple strategies to generate xCT therapies, including developing therapeutic antibodies and testing thousands of small molecular compounds that might block xCT’s activity. Over the next year, they will complete their initial screen of FDA-approved therapies—a strategy that can repurpose drugs which are already known to be safe in patients because they were approved for other diseases. The team is halfway through testing this library of compounds and have already found a few candidates that affect xCT activity. Promising drugs will be assessed in the laboratory with the ultimate goal of being tested in clinical trials.

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Identifying new therapeutic targets for aggressive forms of breast cancer.

Impact

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis. Although TNBC patients benefit from standard chemotherapy, and some fare well with new immunotherapies, overall, they face high recurrence rates and are more likely to develop chemoresistance. There is therefore an urgent need to develop new targeted therapies for these patients.

Progress Thus Far

Dr. Ashworth and his team identified a protein called xCT as a potentially promising therapeutic target for TNBC. This protein serves as a molecular transporter; it sits within the outer membranes of cells, funneling specific molecules into the cell and expelling others. Tumor cells can use it to eject chemotherapies and take in nutrients. While it is dispensable for the function of healthy cells, loss of xCT function is lethal to tumor cells, making it an attractive therapeutic target. Importantly, xCT is present in approximately half of TNBC tumors and high levels are associated with worse outcomes for patients. Over the past year the team pursued two complementary strategies that will help them identify promising xCT therapies. They engineered both a nano sensor and a chemical probe, which will help signal if a drug they are testing is effectively blocking xCT.

What’s next

Dr. Ashworth’s team will pursue multiple strategies to generate xCT therapies, including developing therapeutic antibodies and testing thousands of small molecular compounds that might block xCT’s activity. Over the next year, they will complete their initial screen of FDA-approved therapies—a strategy that can repurpose drugs which are already known to be safe in patients because they were approved for other diseases. The team is halfway through testing this library of compounds and have already found a few candidates that affect xCT activity. Promising drugs will be assessed in the laboratory with the ultimate goal of being tested in clinical trials.

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Learn more about Jill Bargonetti at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Jill Bargonetti | Researcher | Breast Cancer Research Foundation

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Learn more about Jill Bargonetti at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Hunter College
Chair, Molecular, Cellular, and Development PhD Program
Department of Biological Sciences Hunter College Belfer Research Building
Graduate Center, City University of New York
Adjunct Assistant Professor, Weill Cornell Medical College Department of Cell Biology

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Jill Bargonetti, PhD has carried out extensive research on the wild-type p53 protein (which assists in the suppression of tumor cells) and oncogenic mutant p53 (which is a tumor promoter). She is also a leader in the field of MDM2 research, studying how MDM2 promotes breast cancer proliferation and the survival of circulating tumor cells. She received her B.A. from SUNY Purchase, her MS and PhD from New York University and her postgraduate training from Columbia University.

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Jill Bargonetti, PhD has carried out extensive research on the wild-type p53 protein (which assists in the suppression of tumor cells) and oncogenic mutant p53 (which is a tumor promoter). She is also a leader in the field of MDM2 research, studying how MDM2 promotes breast cancer proliferation and the survival of circulating tumor cells. She received her B.A. from SUNY Purchase, her MS and PhD from New York University and her postgraduate training from Columbia University. In 1994, she joined the professoriate at The City University of New York (CUNY) at Hunter College and The Graduate Center in the PhD Programs of Biology and Biochemistry and currently holds the title of Full Professor at CUNY along with an adjunct professoriate appointment at the Weill Cornell Medical College in the Department of Cell Biology.

Dr. Bargonetti was awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997 and has received research grants from the American Cancer Society, The Department of Defense, The National Science Foundation (NSF), The National Institutes of Health (NIH), and the Breast Cancer Research Foundation (BCRF). She was a member of the National Cancer Policy Board from 2002 until 2005 (a board of the Institution of Medicine and National Research Council of the National Academies) and served on the NIH Tumor Cell Biology study section from 2012-2018.

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Jill Bargonetti, PhD has carried out extensive research on the wild-type p53 protein (which assists in the suppression of tumor cells) and oncogenic mutant p53 (which is a tumor promoter). She is also a leader in the field of MDM2 research, studying how MDM2 promotes breast cancer proliferation and the survival of circulating tumor cells. She received her B.A. from SUNY Purchase, her MS and PhD from New York University and her postgraduate training from Columbia University. In 1994, she joined the professoriate at The City University of New York (CUNY) at Hunter College and The Graduate Center in the PhD Programs of Biology and Biochemistry and currently holds the title of Full Professor at CUNY along with an adjunct professoriate appointment at the Weill Cornell Medical College in the Department of Cell Biology.

Dr. Bargonetti was awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997 and has received research grants from the American Cancer Society, The Department of Defense, The National Science Foundation (NSF), The National Institutes of Health (NIH), and the Breast Cancer Research Foundation (BCRF). She was a member of the National Cancer Policy Board from 2002 until 2005 (a board of the Institution of Medicine and National Research Council of the National Academies) and served on the NIH Tumor Cell Biology study section from 2012-2018.

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Research area: To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.

Impact: Triple-negative breast cancer (TNBC) is a group of diseases that are difficult to treat and have a high likelihood of spreading to other tissues —a process called metastasis. Part of the challenge is that TNBCs currently have few biomarkers that can be used to detect, diagnose, and manage it. Dr. Bargonetti is studying three critical biomarkers—mtp53, MDMX and MDM2—known to drive TNBC and other types of breast cancer to determine how they can be targeted to kill cancer cells. These studies have the potential to improve early detection and targeted therapeutics with the development of TNBC-associated biomarkers.

Progress Thus Far: Dr. Bargonetti has advanced the understanding of the role mtp53, MDMX, MDM2 in the spread of TNBC. Her  work has shown that: 1) metastatic TNBCs that harbor a mutated p53 protein (mtp53) are sensitive to PARP inhibitors, a class of drugs that target cells with deficient DNA repair;  2) MDM2 and MDMX are often upregulated along with mtp53 in highly metastatic breast cancer; and 3) upregulation of MDMX increases circulating tumor cells (CTCs) thereby facilitating TNBC metastasis. Her team has also developed a novel peptide that targets mtp53.

What’s next: Dr. Bargonetti and her team will continue to explore the mtp53-MDMX-MDM2 axis as a target for development of novel strategies to accurately identify and kill TNBC cells. Specifically, they will further investigate mtp53 as a biomarker for sensitivity to PARP inhibitors as well as other drug combinations, and pursue studies to determine whether MDMX may be a novel marker for liquid biopsy.

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Research area: To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.

Impact: Triple-negative breast cancer (TNBC) is a group of diseases that are difficult to treat and have a high likelihood of spreading to other tissues —a process called metastasis. Part of the challenge is that TNBCs currently have few biomarkers that can be used to detect, diagnose, and manage it. Dr. Bargonetti is studying three critical biomarkers—mtp53, MDMX and MDM2—known to drive TNBC and other types of breast cancer to determine how they can be targeted to kill cancer cells. These studies have the potential to improve early detection and targeted therapeutics with the development of TNBC-associated biomarkers.

Progress Thus Far: Dr. Bargonetti has advanced the understanding of the role mtp53, MDMX, MDM2 in the spread of TNBC. Her  work has shown that: 1) metastatic TNBCs that harbor a mutated p53 protein (mtp53) are sensitive to PARP inhibitors, a class of drugs that target cells with deficient DNA repair;  2) MDM2 and MDMX are often upregulated along with mtp53 in highly metastatic breast cancer; and 3) upregulation of MDMX increases circulating tumor cells (CTCs) thereby facilitating TNBC metastasis. Her team has also developed a novel peptide that targets mtp53.

What’s next: Dr. Bargonetti and her team will continue to explore the mtp53-MDMX-MDM2 axis as a target for development of novel strategies to accurately identify and kill TNBC cells. Specifically, they will further investigate mtp53 as a biomarker for sensitivity to PARP inhibitors as well as other drug combinations, and pursue studies to determine whether MDMX may be a novel marker for liquid biopsy.

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Research area: To develop new ways to target an aggressive form of breast cancer — triple-negative breast cancer (TNBC) — to prevent its growth and metastasis.

Impact: TNBC has few targetable biomarkers that could help determine the most beneficial treatment for each patient. Dr. Bargonetti has identified three biomarkers (mtp53, MDMX, MDM2) that together may lead to targeted treatment for TNBC. These proteins appear to help triple-negative tumors grow and spread – understanding how they intersect on tumor DNA will set the stage for much needed diagnostics and targeted, personalized therapies for TNBC patients.

Current investigation: Dr. Bargonetti is focused on the role played by three critical proteins—mtp53, MDM2, and MDX—in driving TNBC. Since breast tumor cells and highly metastatic breast cancers often express mutated p53 and overexpressed MDM2 and MDMX, her team is determining ways to accurately image tumors and liquid biopsy material to identify and kill cells with mutant p53 and high levels of MDM2 and MDMX.

What she’s learned so far: Dr. Bargonetti’s team discovered that metastatic TNBC that harbor a mutation p53 protein (mtp53) are sensitive to PARP (poly ADP ribose polymerase) inhibitors, a class of drugs that target cells with deficient DNA repair. They have shown that mtp53 associates with PARP (a DNA repair protein) and DNA and is likely responsible for tumor growth.  A second protein (MDMX), when upregulated, drives circulating tumor cells and promotes TNBC metastasis.

What’s next: Dr. Bargonetti and her team will continue to investigate mtp53 as a biomarker to guide treatment with PARP-inhibitors and other combinations of drugs. In addition, they will pursue MDMX as a novel biomarker for liquid biopsy since its presence indicates that tumor cells are no longer at the primary tumor site. The team will continue to investigate the action of MDM2 and explore the mtp53-MDMX-MDM2 axis as a target to develop strategies for imaging TNBC tumors to accurately identify and kill these breast cancer cells.

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Research area: To develop new ways to target an aggressive form of breast cancer — triple-negative breast cancer (TNBC) — to prevent its growth and metastasis.

Impact: TNBC has few targetable biomarkers that could help determine the most beneficial treatment for each patient. Dr. Bargonetti has identified three biomarkers (mtp53, MDMX, MDM2) that together may lead to targeted treatment for TNBC. These proteins appear to help triple-negative tumors grow and spread – understanding how they intersect on tumor DNA will set the stage for much needed diagnostics and targeted, personalized therapies for TNBC patients.

Current investigation: Dr. Bargonetti is focused on the role played by three critical proteins—mtp53, MDM2, and MDX—in driving TNBC. Since breast tumor cells and highly metastatic breast cancers often express mutated p53 and overexpressed MDM2 and MDMX, her team is determining ways to accurately image tumors and liquid biopsy material to identify and kill cells with mutant p53 and high levels of MDM2 and MDMX.

What she’s learned so far: Dr. Bargonetti’s team discovered that metastatic TNBC that harbor a mutation p53 protein (mtp53) are sensitive to PARP (poly ADP ribose polymerase) inhibitors, a class of drugs that target cells with deficient DNA repair. They have shown that mtp53 associates with PARP (a DNA repair protein) and DNA and is likely responsible for tumor growth.  A second protein (MDMX), when upregulated, drives circulating tumor cells and promotes TNBC metastasis.

What’s next: Dr. Bargonetti and her team will continue to investigate mtp53 as a biomarker to guide treatment with PARP-inhibitors and other combinations of drugs. In addition, they will pursue MDMX as a novel biomarker for liquid biopsy since its presence indicates that tumor cells are no longer at the primary tumor site. The team will continue to investigate the action of MDM2 and explore the mtp53-MDMX-MDM2 axis as a target to develop strategies for imaging TNBC tumors to accurately identify and kill these breast cancer cells.

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Professor, Hunter College 
Chair, Molecular, Cellular, and Development PhD Program
Department of Biological Sciences Hunter College Belfer Research Building
Graduate Center, City University of New York 
Adjunct Assistant Professor, Weill Cornell Medical College Department of Cell Biology

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To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.

Impact

Triple-negative breast cancer (TNBC) is a group of diseases that are difficult to treat and have a high likelihood of spreading to other tissues —a process called metastasis. Part of the challenge is that TNBCs currently have few biomarkers that can be used to detect, diagnose, and manage it. TNBCs can evade DNA damaging agents such as PARP inhibitors by adapting their DNA damage repair system—this adaptation often results in genomic instability.  Dr. Bargonetti is studying three critical biomarkers—mtp53, MDMX and MDM2—known to drive TNBC and other types of breast cancer to determine their role in this adaptation.   Since these biomarkers correlate with increased sensitivity to PARP inhibitors, Dr. Bargonetti’s lab is focused on determining the molecular mechanisms involved in their interaction. These studies will potentially uncover novel ways to exploit the mtp53-MDMX-MDM2 axis and target the breast cancers that use it—thus providing druggable targets in a breast cancer subtype with limited therapeutic options.

Project Thus Far

Dr. Bargonetti has advanced the understanding of the role mtp53, MDMX, MDM2 in the spread of TNBC. Her work has shown that: 1) metastatic TNBCs that harbor a mutated p53 protein (mtp53) are sensitive to PARP inhibitors; 2) MDM2 and MDMX are often upregulated along with mtp53 in highly metastatic breast cancer; and 3) upregulation of MDMX increases circulating tumor cells (CTCs) thereby facilitating TNBC metastasis. In the last year, the Bargonetti lab demonstrated that PARP inhibition promotes breast cancer cell death and correlates with a progressive reduction in MDMX protein while MDM2 interacts with a critical DNA repair protein. The team has also developed laboratory models in which these proteins have been manipulated in order to delve further into how they influence PARP inhibitor sensitivity.

What’s next

Dr. Bargonetti and her team will continue to explore the mtp53-MDMX-MDM2 axis as a target for development of novel strategies to accurately identify and kill TNBC cells. Specifically, they will continue to investigate the molecular mechanisms of PARP inhibitor sensitivity driven by these breast cancer biomarkers.

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To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.

Impact

Triple-negative breast cancer (TNBC) is a group of diseases that are difficult to treat and have a high likelihood of spreading to other tissues —a process called metastasis. Part of the challenge is that TNBCs currently have few biomarkers that can be used to detect, diagnose, and manage it. TNBCs can evade DNA damaging agents such as PARP inhibitors by adapting their DNA damage repair system—this adaptation often results in genomic instability.  Dr. Bargonetti is studying three critical biomarkers—mtp53, MDMX and MDM2—known to drive TNBC and other types of breast cancer to determine their role in this adaptation.   Since these biomarkers correlate with increased sensitivity to PARP inhibitors, Dr. Bargonetti’s lab is focused on determining the molecular mechanisms involved in their interaction. These studies will potentially uncover novel ways to exploit the mtp53-MDMX-MDM2 axis and target the breast cancers that use it—thus providing druggable targets in a breast cancer subtype with limited therapeutic options.

Project Thus Far

Dr. Bargonetti has advanced the understanding of the role mtp53, MDMX, MDM2 in the spread of TNBC. Her work has shown that: 1) metastatic TNBCs that harbor a mutated p53 protein (mtp53) are sensitive to PARP inhibitors; 2) MDM2 and MDMX are often upregulated along with mtp53 in highly metastatic breast cancer; and 3) upregulation of MDMX increases circulating tumor cells (CTCs) thereby facilitating TNBC metastasis. In the last year, the Bargonetti lab demonstrated that PARP inhibition promotes breast cancer cell death and correlates with a progressive reduction in MDMX protein while MDM2 interacts with a critical DNA repair protein. The team has also developed laboratory models in which these proteins have been manipulated in order to delve further into how they influence PARP inhibitor sensitivity.

What’s next

Dr. Bargonetti and her team will continue to explore the mtp53-MDMX-MDM2 axis as a target for development of novel strategies to accurately identify and kill TNBC cells. Specifically, they will continue to investigate the molecular mechanisms of PARP inhibitor sensitivity driven by these breast cancer biomarkers.

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Learn more about Debra L. Barton at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Debra L. Barton | Researcher | Breast Cancer Research Foundation

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Learn more about Debra L. Barton at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Debra Barton, RN, PhD, FAAN has been a funded investigator in oncology symptom management since 2002, having developed, implemented and completed 11 large multi-site intervention trials.  She has developed phase II and III clinical trials in a variety of symptoms including fatigue, hot flashes, peripheral neuropathy, sleep problems, cognitive changes related to chemotherapy, nausea and vomiting, and sexual health, using behavioral interventions such as hypnosis and imagery as well as dietary supplements.

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Debra Barton, RN, PhD, FAAN has been a funded investigator in oncology symptom management since 2002, having developed, implemented and completed 11 large multi-site intervention trials.  She has developed phase II and III clinical trials in a variety of symptoms including fatigue, hot flashes, peripheral neuropathy, sleep problems, cognitive changes related to chemotherapy, nausea and vomiting, and sexual health, using behavioral interventions such as hypnosis and imagery as well as dietary supplements. Three previously completed trials have demonstrated promising positive effects; a topical gel for peripheral neuropathy, American ginseng for cancer related fatigue and vaginal dehydroepiandosterone (DHEA) for vaginal symptoms. She also completed a pilot study showing positive effects on hot flashes from hypnosis alone that were equal to the improvement seen with an antidepressant known to help hot flashes. 

Dr. Barton is currently developing a comprehensive multi-faceted intervention for improving sexual health for women with a history of cancer that involves both pharmacologic and non-pharmacologic components that address physiologic, psychosocial and cognitive variables that impact sexual health. Therefore, her approach to symptom management is to address symptoms from multiple perspectives, using more than one intervention, to reduce symptoms with minimal to no side effects.

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Debra Barton, RN, PhD, FAAN has been a funded investigator in oncology symptom management since 2002, having developed, implemented and completed 11 large multi-site intervention trials. She has developed phase II and III clinical trials in a variety of symptoms including fatigue, hot flashes, peripheral neuropathy, sleep problems, cognitive changes related to chemotherapy, nausea and vomiting, and sexual health, using behavioral interventions such as hypnosis and imagery as well as dietary supplements. Three previously completed trials have demonstrated promising positive effects; a topical gel for peripheral neuropathy, American ginseng for cancer related fatigue and vaginal dehydroepiandosterone (DHEA) for vaginal symptoms. She also completed a pilot study showing positive effects on hot flashes from hypnosis alone that were equal to the improvement seen with an antidepressant known to help hot flashes.

Dr. Barton is currently developing a comprehensive multi-faceted intervention for improving sexual health for women with a history of cancer that involves both pharmacologic and non-pharmacologic components that address physiologic, psychosocial and cognitive variables that impact sexual health. Therefore, her approach to symptom management is to address symptoms from multiple perspectives, using more than one intervention, to reduce symptoms with minimal to no side effects.

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Research Area: Addressing the sexual health needs of breast cancer patients after treatment to improve their quality of life and maintain or restore intimacy.

Impact: Advances in breast cancer therapies have led to a growing number of survivors, however, many women taking anti-estrogen therapies experience unwanted side effects, such as sexual dysfunction, changes in libido, and vaginal discomfort. These effects can be so troublesome that some women may stop therapy before completing the recommended course. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to help women and their partners regain intimacy, which is often put on hold during treatment. Management of these issues will help to improve patients' quality of life during and after treatment.

Progress Thus Far: Dr. Barton has identified strategies to improve vaginal symptoms and body image, demonstrating that a vaginal gel and mind-body therapy helped both symptoms, respectively. In addition, she and her team have conducted and analyzed the data from a study of 230 women with breast cancer evaluating the use of an antidepressant (bupropion) to improve sexual energy and desire. The results show that patients that have completed treatment for breast cancer have very low sexual function scores in many areas. They also completed the development of a partner intervention workbook to improve intimacy and communication.

What's next: Dr. Barton and her colleagues will continue to analyze the data from their study to gain a better understanding of the efficacy of bupropion to alleviate intimacy issues for breast cancer survivors. In addition, her team will explore methods to deliver their partner intervention workbook to breast cancer patients following treatment—since many patients do not have insurance coverage or access to specialists, they hope to make this intervention/psychosocial support available in an equitable and accessible manner to as many patients as possible.  Lastly, Dr. Barton will embark on a new pilot study using an interactive phone application to deliver cognitive behavioral therapy interventions to improve sleep outcomes in cancer survivors.

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Research Area: Addressing the sexual health needs of breast cancer patients after treatment to improve their quality of life and maintain or restore intimacy.

Impact: Advances in breast cancer therapies have led to a growing number of survivors, however, many women taking anti-estrogen therapies experience unwanted side effects, such as sexual dysfunction, changes in libido, and vaginal discomfort. These effects can be so troublesome that some women may stop therapy before completing the recommended course. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to help women and their partners regain intimacy, which is often put on hold during treatment. Management of these issues will help to improve patients' quality of life during and after treatment.

Progress Thus Far: Dr. Barton has identified strategies to improve vaginal symptoms and body image, demonstrating that a vaginal gel and mind-body therapy helped both symptoms, respectively. In addition, she and her team have conducted and analyzed the data from a study of 230 women with breast cancer evaluating the use of an antidepressant (bupropion) to improve sexual energy and desire. The results show that patients that have completed treatment for breast cancer have very low sexual function scores in many areas. They also completed the development of a partner intervention workbook to improve intimacy and communication.

What's next: Dr. Barton and her colleagues will continue to analyze the data from their study to gain a better understanding of the efficacy of bupropion to alleviate intimacy issues for breast cancer survivors. In addition, her team will explore methods to deliver their partner intervention workbook to breast cancer patients following treatment—since many patients do not have insurance coverage or access to specialists, they hope to make this intervention/psychosocial support available in an equitable and accessible manner to as many patients as possible.  Lastly, Dr. Barton will embark on a new pilot study using an interactive phone application to deliver cognitive behavioral therapy interventions to improve sleep outcomes in cancer survivors.

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Research goal: Improving the sexual health of female breast cancer patients after treatment.

Impact: Advances in breast cancer therapies have led to a growing number of survivors, however, these therapies can lead to consequences for patients such as vaginal pain and dryness and decreased sexual desire. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to manage these problems to improve patients’ quality of life during and after treatment.

Current investigation: Dr. Barton and her colleagues are testing interventions that address four key predictors of sexual health in survivorship: vaginal symptoms, body image, sexual energy/libido, and partner issues. They are also analyzing the results of their large study which evaluated the efficacy of an antidepressant drug in alleviating symptoms of reduced sexual energy/libido.

What she’s accomplished so far: Dr. Barton has identified strategies to improve vaginal symptoms and body image, demonstrating that a vaginal gel and mind-body therapy helped both symptoms, respectively. In addition, she and her team have conducted a large study of 230 women with breast cancer to evaluate the use of an antidepressant – bupropion, that works through a chemical in the brain associated with passion (dopamine) - to improve sexual energy and desire. They have also developed a partner intervention to improve intimacy and communication.

What’s next: Her team will continue to analyze the data obtained from the clinical trial to evaluate bupropion as a method to improve sexual desire and intimacy. Over the next year, Dr. Barton and her colleagues will explore methods to deliver their partner intervention to patients – since many patients do not have insurance coverage or access to specialists, they hope to make this intervention/ psychosocial support available in an equitable and accessible manner to as many patients as possible.  To accomplish this, they will develop a method of delivering the partner intervention through a phone app - this can potentially provide effective interventions to the community and improve the quality of life for patients after treatment.

# data[].attributes.field_full_research_summary.processed
Research goal: Improving the sexual health of female breast cancer patients after treatment.

Impact: Advances in breast cancer therapies have led to a growing number of survivors, however, these therapies can lead to consequences for patients such as vaginal pain and dryness and decreased sexual desire. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to manage these problems to improve patients’ quality of life during and after treatment.

Current investigation: Dr. Barton and her colleagues are testing interventions that address four key predictors of sexual health in survivorship: vaginal symptoms, body image, sexual energy/libido, and partner issues. They are also analyzing the results of their large study which evaluated the efficacy of an antidepressant drug in alleviating symptoms of reduced sexual energy/libido.

What she’s accomplished so far: Dr. Barton has identified strategies to improve vaginal symptoms and body image, demonstrating that a vaginal gel and mind-body therapy helped both symptoms, respectively. In addition, she and her team have conducted a large study of 230 women with breast cancer to evaluate the use of an antidepressant – bupropion, that works through a chemical in the brain associated with passion (dopamine) - to improve sexual energy and desire. They have also developed a partner intervention to improve intimacy and communication.

What’s next: Her team will continue to analyze the data obtained from the clinical trial to evaluate bupropion as a method to improve sexual desire and intimacy. Over the next year, Dr. Barton and her colleagues will explore methods to deliver their partner intervention to patients – since many patients do not have insurance coverage or access to specialists, they hope to make this intervention/ psychosocial support available in an equitable and accessible manner to as many patients as possible.  To accomplish this, they will develop a method of delivering the partner intervention through a phone app - this can potentially provide effective interventions to the community and improve the quality of life for patients after treatment.

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McMahan-McKinley Endowed Professor in Gerontology 

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If not for BCRF, important health related quality of life issues would not be addressed in innovative ways. BCRF makes it possible for research to be done more nimbly; to be able to use evidence in real time to advance symptom science and address gaps in psychosocial cancer care. — Dr. Barton

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If not for BCRF, important health related quality of life issues would not be addressed in innovative ways. BCRF makes it possible for research to be done more nimbly; to be able to use evidence in real time to advance symptom science and address gaps in psychosocial cancer care. — Dr. Barton

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Addressing the sexual health needs of breast cancer patients after treatment to improve their quality of life and maintain or restore intimacy.

Impact

Advances in breast cancer therapies have led to a growing number of survivors, however, many women taking anti-estrogen therapies experience unwanted side effects, such as sexual dysfunction, changes in libido, and vaginal discomfort. These effects can be so troublesome that some women may stop therapy before completing the recommended course. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to help women and their partners regain intimacy, which is often put on hold during treatment. Management of these issues will help to improve patients' quality of life during and after treatment.

Progress Thus Far

Dr. Barton’s team developed an interactive workbook for couples to address communication and intimacy, as well as a phone app for sleep. Both interventions are being evaluated for how helpful they are and whether they positively impact desired outcomes. Thus far, participants are highly appreciative of both the workbook and the phone app, providing data that they are helpful but also convenient and easy to use.

What's next

In addition to evaluating the effectiveness of the combined workbook and sleep app interventions, the team also developed a study to evaluate another two-component intervention for sexual health that addresses vaginal symptoms, self-image and libido. This study is going through institutional approval processes and should open in 2022. Importantly, this work will provide the foundation on which the team will eventually add the couples' component, to have a truly comprehensive intervention bundle for sexual health.

# data[].attributes.field_research.processed
Addressing the sexual health needs of breast cancer patients after treatment to improve their quality of life and maintain or restore intimacy.

Impact

Advances in breast cancer therapies have led to a growing number of survivors, however, many women taking anti-estrogen therapies experience unwanted side effects, such as sexual dysfunction, changes in libido, and vaginal discomfort. These effects can be so troublesome that some women may stop therapy before completing the recommended course. Unfortunately, this important aspect of survivorship is not often addressed during routine medical care. Dr. Barton is investigating ways to help women and their partners regain intimacy, which is often put on hold during treatment. Management of these issues will help to improve patients' quality of life during and after treatment.

Progress Thus Far

Dr. Barton’s team developed an interactive workbook for couples to address communication and intimacy, as well as a phone app for sleep. Both interventions are being evaluated for how helpful they are and whether they positively impact desired outcomes. Thus far, participants are highly appreciative of both the workbook and the phone app, providing data that they are helpful but also convenient and easy to use.

What's next

In addition to evaluating the effectiveness of the combined workbook and sleep app interventions, the team also developed a study to evaluate another two-component intervention for sexual health that addresses vaginal symptoms, self-image and libido. This study is going through institutional approval processes and should open in 2022. Importantly, this work will provide the foundation on which the team will eventually add the couples' component, to have a truly comprehensive intervention bundle for sexual health.

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Learn more about Robert Benezra at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Robert Benezra | Researcher | Breast Cancer Research Foundation

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Learn more about Robert Benezra at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Member, Department of Cell Biology and Genetics<br />

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Robert Benezra, PhD, is a Member at Memorial Sloan Kettering Cancer in the Department of Cell Biology and a Professor of Biology at Cornell Graduate School of Medical Sciences in New York City. As a postdoctoral fellow he identified the Id proteins as dominant negative regulators of the helix-loop-helix protein family and has since gone on to identify these proteins as key regulators of tumor growth, angiogenesis and metastasis.

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Robert Benezra, PhD, is a Member at Memorial Sloan Kettering Cancer in the Department of Cell Biology and a Professor of Biology at Cornell Graduate School of Medical Sciences in New York City. As a postdoctoral fellow he identified the Id proteins as dominant negative regulators of the helix-loop-helix protein family and has since gone on to identify these proteins as key regulators of tumor growth, angiogenesis and metastasis. In addition, while at Sloan Kettering, Benezra and his colleagues identified the first human mitotic checkpoint gene, hsMad2, and demonstrated that its deregulation leads to chromosome instability, tumor progression and drug resistance. His program continues to focus on the molecular basis of tumor angiogenesis, tumor instability and metastasis. His current project supported by BCRF is to explore the therapeutic potential of a novel agent targeting the Id proteins for the treatment of aggressive triple negative breast cancers.

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Robert Benezra, PhD, is a Member at Memorial Sloan Kettering Cancer in the Department of Cell Biology and a Professor of Biology at Cornell Graduate School of Medical Sciences in New York City. As a postdoctoral fellow he identified the Id proteins as dominant negative regulators of the helix-loop-helix protein family and has since gone on to identify these proteins as key regulators of tumor growth, angiogenesis and metastasis. In addition, while at Sloan Kettering, Benezra and his colleagues identified the first human mitotic checkpoint gene, hsMad2, and demonstrated that its deregulation leads to chromosome instability, tumor progression and drug resistance. His program continues to focus on the molecular basis of tumor angiogenesis, tumor instability and metastasis. His current project supported by BCRF is to explore the therapeutic potential of a novel agent targeting the Id proteins for the treatment of aggressive triple negative breast cancers.

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Goal: To discover new therapeutic targets to treat aggressive breast cancers.

Impact: Metastatic breast cancer (MBC), which is cancer that has spread from the breast to other tissues in the body, is the leading cause of breast cancer deaths. Dr. Benezra’s work is focused on an agent called AGX51 that has been shown to block tumor growth and metastasis in laboratory studies. His work could inform the development of a new class of well-tolerated, anti-metastatic drugs.

What’s next: He and his team will confirm the mechanism of action of AGX51 and investigate how cancer cells could potentially become resistant to its effects.

MBC is incurable and treatment options are desperately needed. Dr. Benezra is studying the role of a type of protein in breast tumors and how they contribute to drug resistance. He and his team are continuing to study AGX51, an agent that reduces levels of these proteins, which have been identified as potential therapeutic targets to prevent metastasis.

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Goal: To discover new therapeutic targets to treat aggressive breast cancers.

Impact: Metastatic breast cancer (MBC), which is cancer that has spread from the breast to other tissues in the body, is the leading cause of breast cancer deaths. Dr. Benezra’s work is focused on an agent called AGX51 that has been shown to block tumor growth and metastasis in laboratory studies. His work could inform the development of a new class of well-tolerated, anti-metastatic drugs.

What’s next: He and his team will confirm the mechanism of action of AGX51 and investigate how cancer cells could potentially become resistant to its effects.

MBC is incurable and treatment options are desperately needed. Dr. Benezra is studying the role of a type of protein in breast tumors and how they contribute to drug resistance. He and his team are continuing to study AGX51, an agent that reduces levels of these proteins, which have been identified as potential therapeutic targets to prevent metastasis.

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Research area: Identifying new therapeutic agents that effectively inhibit the spread of breast cancer (metastasis).

Impact: Metastatic breast cancer (MBC), which is breast cancer that has spread to other sites in the body, is incurable and is the leading cause of breast cancer deaths. Thus, new treatment strategies are urgently needed that can prevent metastasis from occurring. Dr. Benezra is pursuing novel therapeutic targets for the treatment of MBC. He aims to apply his findings to the development of a new class of anti-metastatic drugs.

Current investigation: He and his colleagues are studying a class of proteins called inhibitor of DNA-binding proteins (ID proteins) as potential therapeutic targets to prevent metastasis. ID proteins are frequently overexpressed in breast cancer and have been implicated in breast cancer tumor growth and metastasis. Previous laboratory studies found that genetic knockdown of ID genes resulted in a reduction in tumor growth and lung metastases.

What he’s learned accomplished so far: Dr. Benezra has developed targeted anti-ID therapy, AGX51, which was shown to reduce lung metastases and cancer cell viability in laboratory studies.

What’s next: He and his team study the role of ID proteins and continue their characterization of AGX51. They propose to study whether ID proteins are the primary targets of AGX51 and how cancer cells could potentially become resistant to the drug. They will also investigate the nature of ID-expressing cells and how they contribute to chemoresistance.

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Research area: Identifying new therapeutic agents that effectively inhibit the spread of breast cancer (metastasis).

Impact: Metastatic breast cancer (MBC), which is breast cancer that has spread to other sites in the body, is incurable and is the leading cause of breast cancer deaths. Thus, new treatment strategies are urgently needed that can prevent metastasis from occurring. Dr. Benezra is pursuing novel therapeutic targets for the treatment of MBC. He aims to apply his findings to the development of a new class of anti-metastatic drugs.

Current investigation: He and his colleagues are studying a class of proteins called inhibitor of DNA-binding proteins (ID proteins) as potential therapeutic targets to prevent metastasis. ID proteins are frequently overexpressed in breast cancer and have been implicated in breast cancer tumor growth and metastasis. Previous laboratory studies found that genetic knockdown of ID genes resulted in a reduction in tumor growth and lung metastases.

What he’s learned accomplished so far: Dr. Benezra has developed targeted anti-ID therapy, AGX51, which was shown to reduce lung metastases and cancer cell viability in laboratory studies.

What’s next: He and his team study the role of ID proteins and continue their characterization of AGX51. They propose to study whether ID proteins are the primary targets of AGX51 and how cancer cells could potentially become resistant to the drug. They will also investigate the nature of ID-expressing cells and how they contribute to chemoresistance.

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Member, Department of Cell Biology and Genetics

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If not for BCRF, I never would have been able to make the transition from basic scientist to drug developer and have the chance to ready a novel therapy for clinical application. — Dr. Benezra

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If not for BCRF, I never would have been able to make the transition from basic scientist to drug developer and have the chance to ready a novel therapy for clinical application. — Dr. Benezra

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Discovering new therapeutic targets to treat aggressive breast cancers.

Impact

Metastatic breast cancer (MBC), which is breast cancer that has spread to other sites in the body, is incurable and is the leading cause of breast cancer deaths. New treatment strategies are urgently needed that can prevent metastasis from occurring. Dr. Benezra’s work is focused on a novel targeted therapy called AGX51 that has been shown to block tumor growth and metastasis in laboratory studies. His work could inform the development of a new class of well-tolerated, anti-metastatic drugs.

Progress Thus Far

Dr. Benezra has made significant progress in identifying how AGX51 works against a key target that is involved in the development and progression of breast cancer. He has discovered that AGX51 kills breast cancer cells through the production of fat-containing molecules called lipids that are toxic to cancer cells but spare normal, healthy tissue. In addition, he and his team have made progress in identifying how certain types of breast cancers can go dormant and escape conventional therapies, ultimately leading to recurrence.

What's next

In the upcoming year, Dr. Benezra will learn more about the lipids that kill cancer cells in response to AGX51. In addition, he is planning to identify markers in cancer stem cells found in multiple cancer types, including triple-negative breast cancer, and to how they function to mediate cancer cell dormancy and drug resistance. Finally, Dr. Benezra hopes to move the AGX51 family of clinical candidates closer to early-phase clinical trials with the help of a grant that he was awarded this year as a result of progress made with BCRF support.

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Discovering new therapeutic targets to treat aggressive breast cancers.

Impact

Metastatic breast cancer (MBC), which is breast cancer that has spread to other sites in the body, is incurable and is the leading cause of breast cancer deaths. New treatment strategies are urgently needed that can prevent metastasis from occurring. Dr. Benezra’s work is focused on a novel targeted therapy called AGX51 that has been shown to block tumor growth and metastasis in laboratory studies. His work could inform the development of a new class of well-tolerated, anti-metastatic drugs.

Progress Thus Far

Dr. Benezra has made significant progress in identifying how AGX51 works against a key target that is involved in the development and progression of breast cancer. He has discovered that AGX51 kills breast cancer cells through the production of fat-containing molecules called lipids that are toxic to cancer cells but spare normal, healthy tissue. In addition, he and his team have made progress in identifying how certain types of breast cancers can go dormant and escape conventional therapies, ultimately leading to recurrence.

What's next

In the upcoming year, Dr. Benezra will learn more about the lipids that kill cancer cells in response to AGX51. In addition, he is planning to identify markers in cancer stem cells found in multiple cancer types, including triple-negative breast cancer, and to how they function to mediate cancer cell dormancy and drug resistance. Finally, Dr. Benezra hopes to move the AGX51 family of clinical candidates closer to early-phase clinical trials with the help of a grant that he was awarded this year as a result of progress made with BCRF support.

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Learn more about Xiang (Shawn) Zhang at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Xiang (Shawn) Zhang | Researcher | Breast Cancer Research Foundation

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Learn more about Xiang (Shawn) Zhang at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Department of Molecular and Cellular Biology
William T. Butler Endowed Chair for Distinguished Faculty
Interim Director, Basic Science Research
Lester and Sue Smith Breast Center

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Dr. Zhang is an Associate tenured Professor at Lester and Sue Smith Breast Center of Baylor College of Medicine. He received his PhD degree from Columbia University under the mentorship of Dr. Lawrence Chasin where he focused on the biology of mRNA splicing.  He then joined Dr. Joan Massague’s laboratory at Memorial Sloan Kettering Cancer Center, where he began to study cancer metastasis. He made several findings using an integrative strategy combining cancer genomics and experimental metastasis approaches.  He was named McNair Scholar in 2011.

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Dr. Zhang is an Associate tenured Professor at Lester and Sue Smith Breast Center of Baylor College of Medicine. He received his PhD degree from Columbia University under the mentorship of Dr. Lawrence Chasin where he focused on the biology of mRNA splicing.  He then joined Dr. Joan Massague’s laboratory at Memorial Sloan Kettering Cancer Center, where he began to study cancer metastasis. He made several findings using an integrative strategy combining cancer genomics and experimental metastasis approaches.  He was named McNair Scholar in 2011. He is also an awardee of the K99/R00 Pathways to Independence Grant from National Cancer Institute. At Baylor College of Medicine, Dr. Zhang continues to investigate biological mechanisms and therapeutic strategies of breast cancer metastasis. His long-term goals are to eradicate latent cancer cells in distant organs, and to reduce the incidence of overt-metastases.

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Dr. Zhang is an Associate tenured Professor at Lester and Sue Smith Breast Center of Baylor College of Medicine. He received his PhD degree from Columbia University under the mentorship of Dr. Lawrence Chasin where he focused on the biology of mRNA splicing.  He then joined Dr. Joan Massague’s laboratory at Memorial Sloan Kettering Cancer Center, where he began to study cancer metastasis. He made several findings using an integrative strategy combining cancer genomics and experimental metastasis approaches.  He was named McNair Scholar in 2011. He is also an awardee of the K99/R00 Pathways to Independence Grant from National Cancer Institute. At Baylor College of Medicine, Dr. Zhang continues to investigate biological mechanisms and therapeutic strategies of breast cancer metastasis. His long-term goals are to eradicate latent cancer cells in distant organs, and to reduce the incidence of overt-metastases.

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Goal: To identify factors that mediate the interaction of tumor cells and the tumor microenvironment in response to immunotherapy in triple-negative breast cancer patients.

Impact: Dr. Zhang is conducting laboratory studies to understand how the interaction of immune cells in and around the tumor affect tumor progression and response to treatment. The results of his studies will provide insight into the response of triple-negative breast cancer (TNBC) patients to immunotherapies such as anti PD-L1 checkpoint inhibitors, as well as possible resistance mechanisms that may arise during the treatment.

What’s next: Dr. Zhang and his team have identified two distinct immune profiles in TNBC and will continue to characterize these subtypes to determine their role in the response to immune checkpoint blockade therapy.

The microenvironment surrounding breast tumors contains a variety of non-tumor cells including multiple kinds of immune cells. These immune cells may play opposite roles: some will fight against tumors, but others enable tumor cells to evade immune surveillance. Dr. Zhang is delineating the different types of immune cell populations in the microenvironment of TNBC tumors and determining how they affect breast tumor progression and decrease the efficacy of immunotherapy.

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Goal: To identify factors that mediate the interaction of tumor cells and the tumor microenvironment in response to immunotherapy in triple-negative breast cancer patients.

Impact: Dr. Zhang is conducting laboratory studies to understand how the interaction of immune cells in and around the tumor affect tumor progression and response to treatment. The results of his studies will provide insight into the response of triple-negative breast cancer (TNBC) patients to immunotherapies such as anti PD-L1 checkpoint inhibitors, as well as possible resistance mechanisms that may arise during the treatment.

What’s next: Dr. Zhang and his team have identified two distinct immune profiles in TNBC and will continue to characterize these subtypes to determine their role in the response to immune checkpoint blockade therapy.

The microenvironment surrounding breast tumors contains a variety of non-tumor cells including multiple kinds of immune cells. These immune cells may play opposite roles: some will fight against tumors, but others enable tumor cells to evade immune surveillance. Dr. Zhang is delineating the different types of immune cell populations in the microenvironment of TNBC tumors and determining how they affect breast tumor progression and decrease the efficacy of immunotherapy.

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Research area: Identification of factors in the tumor microenvironment that can be targeted to increase the efficacy of immunotherapy for patients with triple-negative breast cancer.

Impact: Immunotherapies including immune checkpoint blockade (ICB) with anti-PD-L1 inhibitors have revolutionized treatment of several cancer types. However, the majority of breast cancer patients have not benefited from this progress. Previous research shows that one of the major barriers to effective ICB therapy is the presence of tumor-promoting immune cells in the tumor microenvironment (TME). Importantly, the exact type and nature of these immune cells vary from patient to patient. In this project, Dr. Zhang will investigate how individual breast tumors evolve to enrich specific types of tumor-promoting immune cells. His team will determine methods to precisely identify and block the functions of these cells. Through these investigations, they hope to increase the number of breast cancer patients that can benefit from ICB and other immunotherapies and to extend the concept of precision medicine to include targetable factors in the TME as well.

Current investigation: Dr. Zhang and his colleagues are conducting studies to identify genes and molecules that mediate the communication between cancer cells and immune cells to promote tumor growth and expansion. By interrupting this crosstalk, they hope to enhance the efficacy of immune checkpoint blockade therapy.

What he’s learned so far: Dr. Zhang and his team have categorized triple-negative breast cancer (TNBC) tumors based on the immune cells that infiltrate their TME. They identified two distinct profiles of immune cell populations which exhibited a wide diversity in numbers and qualities across patients—a neutrophil-enriched subtype (NES) and a macrophage-enriched subtype (MES). NES and MES tumors appear to rely on different types of myeloid (blood) cells to escape immunosurveillance suggesting a novel mechanism underlying therapeutic resistance to immunotherapies.

What’s next: In the coming year, -Dr. Zhang and his team will delve into determining how macrophages and neutrophils affect breast tumor progression and prevent a robust response to immunotherapy with checkpoint blockade agents. Utilizing various laboratory models, they will identify genes and molecules that mediate the crosstalk between cancer cells and these immune cells. They will also determine ways to disrupt this crosstalk to enhance immune checkpoint blockade therapy and increase the proportion of patients that may benefit from this treatment.

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Research area: Identification of factors in the tumor microenvironment that can be targeted to increase the efficacy of immunotherapy for patients with triple-negative breast cancer.

Impact: Immunotherapies including immune checkpoint blockade (ICB) with anti-PD-L1 inhibitors have revolutionized treatment of several cancer types. However, the majority of breast cancer patients have not benefited from this progress. Previous research shows that one of the major barriers to effective ICB therapy is the presence of tumor-promoting immune cells in the tumor microenvironment (TME). Importantly, the exact type and nature of these immune cells vary from patient to patient. In this project, Dr. Zhang will investigate how individual breast tumors evolve to enrich specific types of tumor-promoting immune cells. His team will determine methods to precisely identify and block the functions of these cells. Through these investigations, they hope to increase the number of breast cancer patients that can benefit from ICB and other immunotherapies and to extend the concept of precision medicine to include targetable factors in the TME as well.

Current investigation: Dr. Zhang and his colleagues are conducting studies to identify genes and molecules that mediate the communication between cancer cells and immune cells to promote tumor growth and expansion. By interrupting this crosstalk, they hope to enhance the efficacy of immune checkpoint blockade therapy.

What he’s learned so far: Dr. Zhang and his team have categorized triple-negative breast cancer (TNBC) tumors based on the immune cells that infiltrate their TME. They identified two distinct profiles of immune cell populations which exhibited a wide diversity in numbers and qualities across patients—a neutrophil-enriched subtype (NES) and a macrophage-enriched subtype (MES). NES and MES tumors appear to rely on different types of myeloid (blood) cells to escape immunosurveillance suggesting a novel mechanism underlying therapeutic resistance to immunotherapies.

What’s next: In the coming year, -Dr. Zhang and his team will delve into determining how macrophages and neutrophils affect breast tumor progression and prevent a robust response to immunotherapy with checkpoint blockade agents. Utilizing various laboratory models, they will identify genes and molecules that mediate the crosstalk between cancer cells and these immune cells. They will also determine ways to disrupt this crosstalk to enhance immune checkpoint blockade therapy and increase the proportion of patients that may benefit from this treatment.

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Professor, Department of Molecular and Cellular Biology 
William T. Butler Endowed Chair for Distinguished Faculty 
Interim Director, Basic Science Research 
Lester and Sue Smith Breast Center 

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Identifying factors in the tumor microenvironment that can be targeted to increase the efficacy of immunotherapy for patients with triple-negative breast cancer.

Impact

Immunotherapies including immune checkpoint blockade (ICB) with anti-PD-L1 inhibitors have revolutionized treatment of several cancer types. However, the majority of breast cancer patients have not benefited from this progress. The microenvironment surrounding breast tumors contains a variety of non-tumor cells including multiple kinds of immune cells. These immune cells may play opposite roles: some will fight against tumors, but others enable tumor cells to evade immune surveillance. Previous research shows that one of the major barriers to effective ICB therapy is the presence of tumor-promoting immune cells in the tumor microenvironment (TME). Importantly, the exact type and nature of these immune cells vary from patient to patient.  Dr. Zhang is delineating the different types of immune cell populations in the microenvironment of triple-negative breast cancer (TNBC) tumors and determining how they affect breast tumor progression and decrease the efficacy of immunotherapy. Through these investigations, they hope to increase the number of breast cancer patients that can benefit from ICB and other immunotherapies and to extend the concept of precision medicine to include targetable factors in the TME as well.

Progress Thus Far

Dr. Zhang and his team have categorized TNBC tumors based on the immune cells that infiltrate their TME. They identified two distinct profiles of immune cell populations—a neutrophil-enriched subtype (NES) and a macrophage-enriched subtype (MES). NES and MES tumors appear to rely on different types of blood cells to escape immuno-surveillance, suggesting a novel mechanism underlying therapeutic resistance to immunotherapies. In the last year, the team has focused on neutrophils specifically. They found that neutrophils work in cooperation with cancer cells for mutual survival benefit: When cancer cells differentiate and become mobile, a necessary step in tumorigenesis and metastasis, the interaction with neutrophils is altered.

What's next

In the coming year, Dr. Zhang and his team will continue to delve into the dynamic relationship between neutrophils and cancer cells that affects breast tumor progression and prevents a robust response to immunotherapy.. They will perform in-depth studies to decipher how the crosstalk between neutrophils and cancer cells influences the survival of both. In addition, Dr. Zhang and his colleagues hope to identify the types of neutrophils that participate in this crosstalk and exploit these findings to develop novel therapeutic targets to prevent it and potentially increase the efficacy of immunotherapies.

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Identifying factors in the tumor microenvironment that can be targeted to increase the efficacy of immunotherapy for patients with triple-negative breast cancer.

Impact

Immunotherapies including immune checkpoint blockade (ICB) with anti-PD-L1 inhibitors have revolutionized treatment of several cancer types. However, the majority of breast cancer patients have not benefited from this progress. The microenvironment surrounding breast tumors contains a variety of non-tumor cells including multiple kinds of immune cells. These immune cells may play opposite roles: some will fight against tumors, but others enable tumor cells to evade immune surveillance. Previous research shows that one of the major barriers to effective ICB therapy is the presence of tumor-promoting immune cells in the tumor microenvironment (TME). Importantly, the exact type and nature of these immune cells vary from patient to patient.  Dr. Zhang is delineating the different types of immune cell populations in the microenvironment of triple-negative breast cancer (TNBC) tumors and determining how they affect breast tumor progression and decrease the efficacy of immunotherapy. Through these investigations, they hope to increase the number of breast cancer patients that can benefit from ICB and other immunotherapies and to extend the concept of precision medicine to include targetable factors in the TME as well.

Progress Thus Far

Dr. Zhang and his team have categorized TNBC tumors based on the immune cells that infiltrate their TME. They identified two distinct profiles of immune cell populations—a neutrophil-enriched subtype (NES) and a macrophage-enriched subtype (MES). NES and MES tumors appear to rely on different types of blood cells to escape immuno-surveillance, suggesting a novel mechanism underlying therapeutic resistance to immunotherapies. In the last year, the team has focused on neutrophils specifically. They found that neutrophils work in cooperation with cancer cells for mutual survival benefit: When cancer cells differentiate and become mobile, a necessary step in tumorigenesis and metastasis, the interaction with neutrophils is altered.

What's next

In the coming year, Dr. Zhang and his team will continue to delve into the dynamic relationship between neutrophils and cancer cells that affects breast tumor progression and prevents a robust response to immunotherapy.. They will perform in-depth studies to decipher how the crosstalk between neutrophils and cancer cells influences the survival of both. In addition, Dr. Zhang and his colleagues hope to identify the types of neutrophils that participate in this crosstalk and exploit these findings to develop novel therapeutic targets to prevent it and potentially increase the efficacy of immunotherapies.

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Learn more about Norman Wolmark at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Norman Wolmark | Researcher | Breast Cancer Research Foundation

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Learn more about Norman Wolmark at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Department of Surgery
University of Pittsburgh School of Medicine
Director, National Cancer Institute Cooperative Group Clinical Trials
University of Pittsburgh Hillman Cancer Center

On behalf of the National Surgical Adjuvant Breast and Bowel Project (NSABP)

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National Surgical Adjuvant Breast and Bowel Project

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Dr. Norman Wolmark, MD, is Chairman of  NSABP Foundation, a not-for-profit academic research organization with a nearly 60-year history of conducting ground-breaking research studies in breast and colorectal cancer.

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Dr. Norman Wolmark, MD, is Chairman of  NSABP Foundation, a not-for-profit academic research organization with a nearly 60-year history of conducting ground-breaking research studies in breast and colorectal cancer.

He is also Professor and Chairman of Human Oncology at Drexel University School of Medicine. Dr. Wolmark received his medical degree from McGill University of Montreal, and he completed his residency at the University of Pittsburgh. He served a fellowship in Surgical Oncology at Memorial Sloan Kettering Cancer Center, and he later became a cancer expert at the Surgery Branch of the National Cancer Institute.

Dr. Wolmark belongs to numerous prestigious organizations including the American Society of Clinical Oncology, the American Association of Cancer Research, and the American Surgical Association.

Over his near 45-year tenure as a cancer researcher, Dr. Wolmark is extensively published, with more than 400 scientific journal articles and book chapters in print.  He is a widely sought-after speaker and lecturer in his field and serves on the editorial board of the Journal of Women’s Cancer, The Journal of Clinical Oncology, and numerous advisory boards, and as an advisor to oncology programs, societies, and institutes throughout the United States and abroad.

Devoted to the evolution of large randomized clinical trials for the treatment and prevention of breast and bowel cancers, he is also a reviewer for The Journal of Clinical Oncology and the New England Journal of Medicine, and he is an editorial board member of the Journal of Women's Cancer and Clinical Breast Cancer.

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Dr. Norman Wolmark, MD, is Chairman of  NSABP Foundation, a not-for-profit academic research organization with a nearly 60-year history of conducting ground-breaking research studies in breast and colorectal cancer.

He is also Professor and Chairman of Human Oncology at Drexel University School of Medicine. Dr. Wolmark received his medical degree from McGill University of Montreal, and he completed his residency at the University of Pittsburgh. He served a fellowship in Surgical Oncology at Memorial Sloan Kettering Cancer Center, and he later became a cancer expert at the Surgery Branch of the National Cancer Institute.

Dr. Wolmark belongs to numerous prestigious organizations including the American Society of Clinical Oncology, the American Association of Cancer Research, and the American Surgical Association.

Over his near 45-year tenure as a cancer researcher, Dr. Wolmark is extensively published, with more than 400 scientific journal articles and book chapters in print.  He is a widely sought-after speaker and lecturer in his field and serves on the editorial board of the Journal of Women’s Cancer, The Journal of Clinical Oncology, and numerous advisory boards, and as an advisor to oncology programs, societies, and institutes throughout the United States and abroad.

Devoted to the evolution of large randomized clinical trials for the treatment and prevention of breast and bowel cancers, he is also a reviewer for The Journal of Clinical Oncology and the New England Journal of Medicine, and he is an editorial board member of the Journal of Women's Cancer and Clinical Breast Cancer.

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Goal: To understand what drives treatment resistance in patients with HER2-positive breast cancer.

Impact: Dr. Wolmark is conducting laboratory studies to understand why some HER2-positive cancers respond to HER2-targeted drugs and others do not. His findings could inform the development of combination treatments that overcome resistance and improve outcomes for patients with this disease.

What’s next: He and his colleagues will continue to study breast cancer cells that express an altered form of HER2, called p95HER2, that drives tumor progression. They will also identify
resistance biomarkers for HER2-positive metastatic breast cancer patients whose tumors did not respond to standard therapy.

While there are several targeted therapies available for HER2-positive breast cancer, resistance to these treatments is a major clinical challenge. In order to overcome drug resistance and improve patient response, a greater understanding of HER2-targeted drug resistance is needed. Dr. Wolmark’s team is identifying resistance markers and determining optimal drug combinations for more effective treatment of HER2-positive breast cancer.

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Goal: To understand what drives treatment resistance in patients with HER2-positive breast cancer.

Impact: Dr. Wolmark is conducting laboratory studies to understand why some HER2-positive cancers respond to HER2-targeted drugs and others do not. His findings could inform the development of combination treatments that overcome resistance and improve outcomes for patients with this disease.

What’s next: He and his colleagues will continue to study breast cancer cells that express an altered form of HER2, called p95HER2, that drives tumor progression. They will also identify
resistance biomarkers for HER2-positive metastatic breast cancer patients whose tumors did not respond to standard therapy.

While there are several targeted therapies available for HER2-positive breast cancer, resistance to these treatments is a major clinical challenge. In order to overcome drug resistance and improve patient response, a greater understanding of HER2-targeted drug resistance is needed. Dr. Wolmark’s team is identifying resistance markers and determining optimal drug combinations for more effective treatment of HER2-positive breast cancer.

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Research Area: Seeking strategies to reduce resistance to HER2-targeted therapies and improve outcomes in patients with this disease.

Impact: Therapies such as trastuzumab have revolutionized the treatment of HER2-positive breast cancer. Trastuzumab and other HER2-targeted therapies block the pro-tumorigenic actions of HER2 on cancer cells and stimulate an immune response directed against the cells. Nevertheless, only a subset of patients with HER2-positive breast cancer experience a robust response and there is a pressing need to understand why some do not. Dr. Wolmark’s BCRF research aims to discover markers and elucidate mechanisms of resistance to these therapies with the goal of identifying potential companion drugs to prevent it.

Current research: Dr. Wolmark’s team is continuing ongoing work to target an altered form of HER2 called p95HER2, that cannot be targeted by standard-of-care therapeutic antibodies such as trastuzumab. Their goal is to develop new strategies to re-invigorate the immune system to overcome this action of p95HER2. Additionally, they are identifying biomarkers that define HER2-positive tumors that are resistant to standard treatment.

What he’s learned so far: The team has initiated the development of tools to 1) identify the mechanism that may be responsible for why some tumors do not respond to anti-HER2 therapy, and 2) to identify new treatment regimens to overcome these mechanisms of resistance. These tools include the development of an antibody that specifically recognizes p95HER2 and the development of novel model systems from patient tumors to test new therapeutic regimens.

What’s next: Dr. Wolmark and his team will identify resistance biomarkers for HER2-positive metastatic breast cancer patients whose disease did not respond to anti-HER2 therapy by using the tissues, collected in NSABP clinical trial FB-10. Patients enrolled in FB-10 were treated with a new anti-HER2 regimen because they failed treatment with trastuzumab plus pertuzumab, another anti-HER2 antibody. They will also analyze genes that are expressed and activate signaling pathways in response to treatment.​

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Research Area: Seeking strategies to reduce resistance to HER2-targeted therapies and improve outcomes in patients with this disease.

Impact: Therapies such as trastuzumab have revolutionized the treatment of HER2-positive breast cancer. Trastuzumab and other HER2-targeted therapies block the pro-tumorigenic actions of HER2 on cancer cells and stimulate an immune response directed against the cells. Nevertheless, only a subset of patients with HER2-positive breast cancer experience a robust response and there is a pressing need to understand why some do not. Dr. Wolmark’s BCRF research aims to discover markers and elucidate mechanisms of resistance to these therapies with the goal of identifying potential companion drugs to prevent it.

Current research: Dr. Wolmark’s team is continuing ongoing work to target an altered form of HER2 called p95HER2, that cannot be targeted by standard-of-care therapeutic antibodies such as trastuzumab. Their goal is to develop new strategies to re-invigorate the immune system to overcome this action of p95HER2. Additionally, they are identifying biomarkers that define HER2-positive tumors that are resistant to standard treatment.

What he’s learned so far: The team has initiated the development of tools to 1) identify the mechanism that may be responsible for why some tumors do not respond to anti-HER2 therapy, and 2) to identify new treatment regimens to overcome these mechanisms of resistance. These tools include the development of an antibody that specifically recognizes p95HER2 and the development of novel model systems from patient tumors to test new therapeutic regimens.

What’s next: Dr. Wolmark and his team will identify resistance biomarkers for HER2-positive metastatic breast cancer patients whose disease did not respond to anti-HER2 therapy by using the tissues, collected in NSABP clinical trial FB-10. Patients enrolled in FB-10 were treated with a new anti-HER2 regimen because they failed treatment with trastuzumab plus pertuzumab, another anti-HER2 antibody. They will also analyze genes that are expressed and activate signaling pathways in response to treatment.​

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Professor, Department of Surgery
University of Pittsburgh School of Medicine
Director, National Cancer Institute Cooperative Group Clinical Trials
University of Pittsburgh Hillman Cancer Center

On behalf of the National Surgical Adjuvant Breast and Bowel Project (NSABP)

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Understanding what drives treatment response and resistance in patients with HER2-positive breast cancer.

Impact

Therapies such as trastuzumab (Herceptin®) have revolutionized the treatment of HER2-positive breast cancer. Trastuzumab and other HER2-targeted therapies block the pro-tumorigenic actions of HER2 on cancer cells and stimulate an immune response directed against the cells. Nevertheless, only a subset of patients with HER2-positive breast cancer experience a robust response and there is a pressing need to understand why some do not. Dr. Wolmark’s BCRF research aims to discover biomarkers to predict treatment response and to elucidate mechanisms of resistance to therapies.

Progress Thus Far

The team recently identified a variant form of HER2 in some HER2-positive tumors from patients who did not have a robust response to HER2-targeting therapies. They also found that this variant of HER2 suppresses immune responses in these tumors, which may help the tumors “hide” from the immune system.

What’s next

The team is currently assessing the utility of biomarker panels that identify the HER2 variant in patient breast cancer samples, along with other proteins that may interfere with the effectiveness of HER2-targeting therapies. They are also performing imaging analyses of the spatial distribution of immune cells within tumors, to see if that might predict patient response to different types of HER2-targeting therapies. In the coming year, they will explore how HER2 variants drive therapeutic resistance, and how tumors might reduce their production of HER2 as another means of therapeutic escape.

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Understanding what drives treatment response and resistance in patients with HER2-positive breast cancer.

Impact

Therapies such as trastuzumab (Herceptin®) have revolutionized the treatment of HER2-positive breast cancer. Trastuzumab and other HER2-targeted therapies block the pro-tumorigenic actions of HER2 on cancer cells and stimulate an immune response directed against the cells. Nevertheless, only a subset of patients with HER2-positive breast cancer experience a robust response and there is a pressing need to understand why some do not. Dr. Wolmark’s BCRF research aims to discover biomarkers to predict treatment response and to elucidate mechanisms of resistance to therapies.

Progress Thus Far

The team recently identified a variant form of HER2 in some HER2-positive tumors from patients who did not have a robust response to HER2-targeting therapies. They also found that this variant of HER2 suppresses immune responses in these tumors, which may help the tumors “hide” from the immune system.

What’s next

The team is currently assessing the utility of biomarker panels that identify the HER2 variant in patient breast cancer samples, along with other proteins that may interfere with the effectiveness of HER2-targeting therapies. They are also performing imaging analyses of the spatial distribution of immune cells within tumors, to see if that might predict patient response to different types of HER2-targeting therapies. In the coming year, they will explore how HER2 variants drive therapeutic resistance, and how tumors might reduce their production of HER2 as another means of therapeutic escape.

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Learn more about Antonio C. Wolff at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Antonio C. Wolff | Researcher | Breast Cancer Research Foundation

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Learn more about Antonio C. Wolff at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor of Oncology
Member, Breast Cancer Program
Sidney Kimmel Comprehensive Cancer Center
Translational Breast Cancer Research Consortium

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Johns Hopkins University School of Medicine

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Dr. Antonio Wolff is a Professor of Oncology at Johns Hopkins University (JHU) and a member of the Johns Hopkins Kimmel Cancer Center (Baltimore, MD). He received his medical degree at the Universidade Federal do Rio de Janeiro in Brazil and trained in medical oncology at Johns Hopkins.

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Dr. Antonio Wolff is a Professor of Oncology at Johns Hopkins University (JHU) and a member of the Johns Hopkins Kimmel Cancer Center (Baltimore, MD). He received his medical degree at the Universidade Federal do Rio de Janeiro in Brazil and trained in medical oncology at Johns Hopkins. 

He is an Associate Editor of the Journal of Clinical Oncology, Chair of the ECOG-ACRIN Breast Cancer Committee, and Chief Operating Officer for the Translational Breast Cancer Research Consortium (TBCRC). He is a Fellow of the American Society of Clinical Oncology (FASCO) and past Chair of its Clinical Practice Guidelines Committee. 

His research interests include new treatment strategies, the development and implementation of prognostic and predictive biomarkers (tissue, blood, and imaging) in clinical practice, and on how to improve the survivorship experience of breast cancer patients and their caregivers. He is a Susan G. Komen Scholar, recipient of a Cancer Clinical Investigator Team Leadership Award from the US National Cancer Institute, and has been recognized since 2017 by Clarivate Analytics (Thomson Reuters) as one of the world’s most highly cited researchers (top 1% in clinical medicine). He maintains an active clinical practice dedicated to the care of patients with breast cancer and was inducted in 2018 as a member of the JHU Miller Coulson Academy of Clinical Excellence. In 2018, Dr. Wolff was recognized as one of 125 Living the Hopkins Mission Honorees, who were selected for their outstanding dedication to the institution’s core values of excellence and discovery, leadership and integrity, diversity and inclusion, and respect and collegiality, as part of the 125th anniversary celebration of the JHU School of Medicine.

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Dr. Antonio Wolff is a Professor of Oncology at Johns Hopkins University (JHU) and a member of the Johns Hopkins Kimmel Cancer Center (Baltimore, MD). He received his medical degree at the Universidade Federal do Rio de Janeiro in Brazil and trained in medical oncology at Johns Hopkins.

He is an Associate Editor of the Journal of Clinical Oncology, Chair of the ECOG-ACRIN Breast Cancer Committee, and Chief Operating Officer for the Translational Breast Cancer Research Consortium (TBCRC). He is a Fellow of the American Society of Clinical Oncology (FASCO) and past Chair of its Clinical Practice Guidelines Committee.

His research interests include new treatment strategies, the development and implementation of prognostic and predictive biomarkers (tissue, blood, and imaging) in clinical practice, and on how to improve the survivorship experience of breast cancer patients and their caregivers. He is a Susan G. Komen Scholar, recipient of a Cancer Clinical Investigator Team Leadership Award from the US National Cancer Institute, and has been recognized since 2017 by Clarivate Analytics (Thomson Reuters) as one of the world’s most highly cited researchers (top 1% in clinical medicine). He maintains an active clinical practice dedicated to the care of patients with breast cancer and was inducted in 2018 as a member of the JHU Miller Coulson Academy of Clinical Excellence. In 2018, Dr. Wolff was recognized as one of 125 Living the Hopkins Mission Honorees, who were selected for their outstanding dedication to the institution’s core values of excellence and discovery, leadership and integrity, diversity and inclusion, and respect and collegiality, as part of the 125th anniversary celebration of the JHU School of Medicine.

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Goal: To accelerate new treatments to benefit patients through focused clinical trials

Impact: TBCRC trials continue to provide insight into the development of more effective and individualized treatments for various subtypes of breast cancer. Funding from BCRF remains critical to bring together scientific resources and researchers to develop new strategies to reduce the burden of breast cancer. Results from these trials provide valuable insight that will guide personalized treatment for various subtypes of breast cancer.

What’s next: Over the next year, the TBCRC will continue enroll patients  on 15 active TBCRC trials, 2 additional clinical trials will be activated and analysis of the data from the completed trials will continue with subsequent reporting and publication of the results.

Clinical trials are the only way to improve patient outcomes, either through the approval of new drugs or different strategies with existing drugs. The process takes many years and a lot of patient volunteers to ultimately determine if patients are likely to do better with the experimental treatment compared to standard care. The Translational Breast Cancer Research Consortium (TBCRC) was formed to bring advances to patients in the shortest time possible and with a precision medicine approach. It does this by enabling small, specialized, biomarker-based trials that recruit patients from academic clinical research centers around the country. Biospecimens—tumor and blood—are collected and used to identify markers of response, or resistance, to the treatment so that in the end the researchers will know more about which patients are most likely to benefit from the treatment.

# data[].attributes.field_current_research.processed
Goal: To accelerate new treatments to benefit patients through focused clinical trials

Impact: TBCRC trials continue to provide insight into the development of more effective and individualized treatments for various subtypes of breast cancer. Funding from BCRF remains critical to bring together scientific resources and researchers to develop new strategies to reduce the burden of breast cancer. Results from these trials provide valuable insight that will guide personalized treatment for various subtypes of breast cancer.

What’s next: Over the next year, the TBCRC will continue enroll patients  on 15 active TBCRC trials, 2 additional clinical trials will be activated and analysis of the data from the completed trials will continue with subsequent reporting and publication of the results.

Clinical trials are the only way to improve patient outcomes, either through the approval of new drugs or different strategies with existing drugs. The process takes many years and a lot of patient volunteers to ultimately determine if patients are likely to do better with the experimental treatment compared to standard care. The Translational Breast Cancer Research Consortium (TBCRC) was formed to bring advances to patients in the shortest time possible and with a precision medicine approach. It does this by enabling small, specialized, biomarker-based trials that recruit patients from academic clinical research centers around the country. Biospecimens—tumor and blood—are collected and used to identify markers of response, or resistance, to the treatment so that in the end the researchers will know more about which patients are most likely to benefit from the treatment.

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Research Area: Advancing treatments to patients in the shortest time possible through focused clinical trials and identifying markers to improve clinical trial stratification and patient outcomes.

Impact: The Translational Breast Cancer Research Consortium (TBCRC) was formed to enable smaller specialized trials that are rich in correlative studies to advance treatments to patients in the quickest possible time. These studies typically require extensive biospecimen collection, often require specialized imaging, enroll fewer patients across a larger number of centers, and require coordinated planning among lab researchers, clinical trialists, biostatisticians, research coordinators, and advocates.

Current research: The TBCRC, under the leadership of Dr. Wolff, is comprised of 18 major clinical centers and over 300 clinical, laboratory, bioinformatics, and administrative support staff. Each year, TBCRC holds two meetings to discuss new clinical design concepts, trial results and provide feedback to trialists to improve clinical trial design or patient recruitment.

What they’ve accomplished so far: Since the inception of the consortium, 53 clinical trials involving over 5300 patients have been enrolled in TBCRC studies, 36 of which have been completed and/or closed to accrual. Results from the first 30 completed TBCRC trials have been presented at national meetings and 24 of these trials were published in peer-reviewed journals. Overall, TBCRC has had over 141 scientific peer-reviewed presentations and publications.

What’s next: The TBCRC continues to hold regular teleconferences among its five core working groups (WGs): Correlative Science WG, the Triple Negative WG, the HER2 Resistance WG, the Endocrine Resistance WG, and the Locoregional Disease WG. The WGs are designed to foster clinical trial concept development in a collegial, nurturing environment and to enhance cross-institutional collaborations. A Patient Advocacy working group works closely with each clinical working group to ensure that the patient voice is represented in clinical trial design. Over the next year, patient accrual will continue for 15 active TBCRC trials, 2 additional clinical trials will be activated and analysis of the data from the completed trials will continue with subsequent reporting and publication of the results.

# data[].attributes.field_full_research_summary.processed
Research Area: Advancing treatments to patients in the shortest time possible through focused clinical trials and identifying markers to improve clinical trial stratification and patient outcomes.

Impact: The Translational Breast Cancer Research Consortium (TBCRC) was formed to enable smaller specialized trials that are rich in correlative studies to advance treatments to patients in the quickest possible time. These studies typically require extensive biospecimen collection, often require specialized imaging, enroll fewer patients across a larger number of centers, and require coordinated planning among lab researchers, clinical trialists, biostatisticians, research coordinators, and advocates.

Current research: The TBCRC, under the leadership of Dr. Wolff, is comprised of 18 major clinical centers and over 300 clinical, laboratory, bioinformatics, and administrative support staff. Each year, TBCRC holds two meetings to discuss new clinical design concepts, trial results and provide feedback to trialists to improve clinical trial design or patient recruitment.

What they’ve accomplished so far: Since the inception of the consortium, 53 clinical trials involving over 5300 patients have been enrolled in TBCRC studies, 36 of which have been completed and/or closed to accrual. Results from the first 30 completed TBCRC trials have been presented at national meetings and 24 of these trials were published in peer-reviewed journals. Overall, TBCRC has had over 141 scientific peer-reviewed presentations and publications.

What’s next: The TBCRC continues to hold regular teleconferences among its five core working groups (WGs): Correlative Science WG, the Triple Negative WG, the HER2 Resistance WG, the Endocrine Resistance WG, and the Locoregional Disease WG. The WGs are designed to foster clinical trial concept development in a collegial, nurturing environment and to enhance cross-institutional collaborations. A Patient Advocacy working group works closely with each clinical working group to ensure that the patient voice is represented in clinical trial design. Over the next year, patient accrual will continue for 15 active TBCRC trials, 2 additional clinical trials will be activated and analysis of the data from the completed trials will continue with subsequent reporting and publication of the results.

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Professor of Oncology
Member, Breast Cancer Program
Sidney Kimmel Comprehensive Cancer Center
Translational Breast Cancer Research Consortium

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Accelerating new treatments to benefit patients through focused clinical trials.

Impact

As our understanding of the complexity of breast cancer continues to evolve, clinical research requires the design of smaller, focused trials that are enriched with studies to reveal the underlying biology. The Translational Breast Cancer Research Consortium (TBCRC) was created to address this unmet need. TBCRC trials often include novel combinations of drugs, or they address highly specific questions that would go unanswered in larger, pharma-initiated studies. These studies are typically intensive in biospecimen acquisition, require specialized imaging, enroll fewer patients across a larger number of centers, and require coordinated planning among lab researchers, clinical trialists, biostatisticians, research coordinators, and patient advocates. Under the leadership of Dr. Antonio Wolff, TBCRC coalesces 18 leading clinical centers across the United States to organize these trials, fostering collaboration among the greatest minds in breast cancer.

Progress Thus Far

To date, TBCRC has approved 63 clinical trials. From these studies, over 6,200 patients participated in important clinical research. BCRF is a primary funder of TBCRC, and its contributions total over $21 million. This support helped yield 150-plus scientific peer-reviewed presentations and publications from TBCRC. These findings have been shared with the global breast cancer community and contributed to a more nuanced understanding of breast cancer progression and treatment.

What’s next

Over the next year, TBCRC will continue to enroll patients on 15 active TBCRC trials, and four were recently approved. Active trials include explorations of treatment response in invasive lobular carcinoma, the addition of exercise treatment to therapy, and new immunotherapeutic treatment strategies.

# data[].attributes.field_research.processed
Accelerating new treatments to benefit patients through focused clinical trials.

Impact

As our understanding of the complexity of breast cancer continues to evolve, clinical research requires the design of smaller, focused trials that are enriched with studies to reveal the underlying biology. The Translational Breast Cancer Research Consortium (TBCRC) was created to address this unmet need. TBCRC trials often include novel combinations of drugs, or they address highly specific questions that would go unanswered in larger, pharma-initiated studies. These studies are typically intensive in biospecimen acquisition, require specialized imaging, enroll fewer patients across a larger number of centers, and require coordinated planning among lab researchers, clinical trialists, biostatisticians, research coordinators, and patient advocates. Under the leadership of Dr. Antonio Wolff, TBCRC coalesces 18 leading clinical centers across the United States to organize these trials, fostering collaboration among the greatest minds in breast cancer.

Progress Thus Far

To date, TBCRC has approved 63 clinical trials. From these studies, over 6,200 patients participated in important clinical research. BCRF is a primary funder of TBCRC, and its contributions total over $21 million. This support helped yield 150-plus scientific peer-reviewed presentations and publications from TBCRC. These findings have been shared with the global breast cancer community and contributed to a more nuanced understanding of breast cancer progression and treatment.

What’s next

Over the next year, TBCRC will continue to enroll patients on 15 active TBCRC trials, and four were recently approved. Active trials include explorations of treatment response in invasive lobular carcinoma, the addition of exercise treatment to therapy, and new immunotherapeutic treatment strategies.

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Learn more about Julienne E. Bower at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Julienne E. Bower | Researcher | Breast Cancer Research Foundation

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Learn more about Julienne E. Bower at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Psychology and Psychiatry/Biobehavioral Sciences
Research Scientist, Cousins Center for Psychoneuroimmunology
David Geffen School of Medicine

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Julienne E. Bower, PhD is a nationally recognized expert on biobehavioral processes in breast cancer and their impact on health and well-being.  She has conducted pioneering work on neuroimmune interactions in breast cancer survivors, focusing on immune mechanisms for behavioral symptoms such as cancer-related fatigue.  Her research also examines the impact of psychosocial stress on behavioral and biological outcomes in cancer populations, including effects on inflammation and the tumor microenvironment.  Dr.

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Julienne E. Bower, PhD is a nationally recognized expert on biobehavioral processes in breast cancer and their impact on health and well-being.  She has conducted pioneering work on neuroimmune interactions in breast cancer survivors, focusing on immune mechanisms for behavioral symptoms such as cancer-related fatigue.  Her research also examines the impact of psychosocial stress on behavioral and biological outcomes in cancer populations, including effects on inflammation and the tumor microenvironment.  Dr. Bower's current BCRF funded research, conducted in collaboration with BCRF co-grantee Steven Cole is designed to identify the upstream neural processes that regulate inflammatory activity and how these can be modulated by mind-body interventions.  Dr. Bower is an Associate Professor in the UCLA Department of Psychology and the Department of Psychiatry and Biobehavioral Sciences and is also a member of the Jonsson Comprehensive Cancer Center and the Norman Cousins Center for Psychoneuroimmunology.

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Julienne E. Bower, PhD is a nationally recognized expert on biobehavioral processes in breast cancer and their impact on health and well-being.  She has conducted pioneering work on neuroimmune interactions in breast cancer survivors, focusing on immune mechanisms for behavioral symptoms such as cancer-related fatigue.  Her research also examines the impact of psychosocial stress on behavioral and biological outcomes in cancer populations, including effects on inflammation and the tumor microenvironment.  Dr. Bower's current BCRF funded research, conducted in collaboration with BCRF co-grantee Steven Cole is designed to identify the upstream neural processes that regulate inflammatory activity and how these can be modulated by mind-body interventions.  Dr. Bower is an Associate Professor in the UCLA Department of Psychology and the Department of Psychiatry and Biobehavioral Sciences and is also a member of the Jonsson Comprehensive Cancer Center and the Norman Cousins Center for Psychoneuroimmunology.

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Research Area:  Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far: Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

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Research Area:  Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far: Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_full_research_summary.value
Research Area:  Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Research Thus Far: Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_full_research_summary.processed
Research Area:  Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Research Thus Far: Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

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Professor, Psychology and Psychiatry/Biobehavioral Sciences
Research Scientist, Cousins Center for Psychoneuroimmunology
David Geffen School of Medicine

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Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact

Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far

Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. Building on their recent findings that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system, they have established a laboratory model system to test how stimulation impacts breast cancer growth and metastasis. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next

The team will continue to optimize the models they developed and determine whether manipulation of the reward system can impact the propensity towards metastasis and how neural and cellular mechanisms are involved. These studies will ultimately help to refine clinical interventions that have the potential to enhance reward-promoting effects in breast cancer patients. They will also expand the use of novel digital approaches for delivering behavioral interventions to more effectively reach a broad and diverse range of women with breast cancer. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_research.processed
Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact

Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Bower and Cole are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far

Drs. Bower and Cole are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. Building on their recent findings that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system, they have established a laboratory model system to test how stimulation impacts breast cancer growth and metastasis. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next

The team will continue to optimize the models they developed and determine whether manipulation of the reward system can impact the propensity towards metastasis and how neural and cellular mechanisms are involved. These studies will ultimately help to refine clinical interventions that have the potential to enhance reward-promoting effects in breast cancer patients. They will also expand the use of novel digital approaches for delivering behavioral interventions to more effectively reach a broad and diverse range of women with breast cancer. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

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Learn more about Myles Brown at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Myles Brown | Researcher | Breast Cancer Research Foundation

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Learn more about Myles Brown at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Emil Frei III Professor of Medicine
Director, Center for Functional Cancer Epigenetics
Dana-Farber Cancer Institute

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Myles Brown, MD is Director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. He obtained his BS in Biology from Yale and his MD from Johns Hopkins. Following training in internal medicine at the Brigham and Women’s Hospital, a fellowship in medical oncology at the Dana-Farber and postdoctoral research at MIT, he joined the staff of the Dana-Farber and the faculty of Harvard Medical School. Dr.

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Myles Brown, MD is Director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. He obtained his BS in Biology from Yale and his MD from Johns Hopkins. Following training in internal medicine at the Brigham and Women’s Hospital, a fellowship in medical oncology at the Dana-Farber and postdoctoral research at MIT, he joined the staff of the Dana-Farber and the faculty of Harvard Medical School. Dr. Brown's research is focused on understanding the factors underlying the hormone dependence of breast and prostate cancers. He is recognized for three seminal discoveries including the role of p160 co-activators in steroid receptor action; the dynamic nature of co-regulator function; and the predominance of steroid receptors as enhancer- rather than promoter-binding factors.

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Myles Brown, MD is Director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. He obtained his BS in Biology from Yale and his MD from Johns Hopkins. Following training in internal medicine at the Brigham and Women’s Hospital, a fellowship in medical oncology at the Dana-Farber and postdoctoral research at MIT, he joined the staff of the Dana-Farber and the faculty of Harvard Medical School. Dr. Brown's research is focused on understanding the factors underlying the hormone dependence of breast and prostate cancers. He is recognized for three seminal discoveries including the role of p160 co-activators in steroid receptor action; the dynamic nature of co-regulator function; and the predominance of steroid receptors as enhancer- rather than promoter-binding factors.

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Research Area: Combatting drug resistance in triple negative breast cancer through new strategies for combination therapies.

Impact: Triple negative breast cancer (TNBC) is an aggressive subtype, and while chemotherapy and immunotherapy are successful in some patients, many develop metastasis and succumb to their disease. This is partly due to the diversity of TNBC tumors—no single therapy will be appropriate for all TNBC patients. The overarching goal of Dr. Myles Brown’s work is to discover new treatments for TNBC by further stratifying tumors into new subtypes, which can in turn reveal new therapeutic targets. For example, some TNBC tumors may be driven by the gene FGFR, which can promote growth and metastatic spread. This suggests that patients with FGFR-positive tumors could be treated with an FGFR-targeted therapy, but clinical trials have been disappointing thus far due to drug resistance.

Progress Thus Far: The team is interested in learning why FGFR-positive TNBC tumors are resistant to FGFR-targeted therapy, and their work culminated in several exciting breakthroughs that were recently published in the journal, Nature Cell Biology. They discovered that high amounts of FGFR seen in some TNBC tumors alters the activity of several genes at once, reprogramming the cells in a way that cannot be treated by targeting a single gene. They further discovered that the activated genes contribute to a change in tumor cell metabolism, circumventing the cells’ dependence on FGFR, and making them resistant to FGFR-targeting therapies.

What’s Next: In the coming year the team will conduct molecular analysis in patient-derived tumors to confirm that their findings. In addition, they will explore the therapeutic potential of combining FGFR inhibitors with therapies that affect metabolism and the genetic reprogramming they encountered in FGFR-resistant cells.

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Research Area: Combatting drug resistance in triple negative breast cancer through new strategies for combination therapies.

Impact: Triple negative breast cancer (TNBC) is an aggressive subtype, and while chemotherapy and immunotherapy are successful in some patients, many develop metastasis and succumb to their disease. This is partly due to the diversity of TNBC tumors—no single therapy will be appropriate for all TNBC patients. The overarching goal of Dr. Myles Brown’s work is to discover new treatments for TNBC by further stratifying tumors into new subtypes, which can in turn reveal new therapeutic targets. For example, some TNBC tumors may be driven by the gene FGFR, which can promote growth and metastatic spread. This suggests that patients with FGFR-positive tumors could be treated with an FGFR-targeted therapy, but clinical trials have been disappointing thus far due to drug resistance.

Progress Thus Far: The team is interested in learning why FGFR-positive TNBC tumors are resistant to FGFR-targeted therapy, and their work culminated in several exciting breakthroughs that were recently published in the journal, Nature Cell Biology. They discovered that high amounts of FGFR seen in some TNBC tumors alters the activity of several genes at once, reprogramming the cells in a way that cannot be treated by targeting a single gene. They further discovered that the activated genes contribute to a change in tumor cell metabolism, circumventing the cells’ dependence on FGFR, and making them resistant to FGFR-targeting therapies.

What’s Next: In the coming year the team will conduct molecular analysis in patient-derived tumors to confirm that their findings. In addition, they will explore the therapeutic potential of combining FGFR inhibitors with therapies that affect metabolism and the genetic reprogramming they encountered in FGFR-resistant cells.

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Research area: Development of novel therapies for drug-resistant and aggressive breast cancers

Impact: While there are effective targeted therapies for breast cancer that are driven by estrogen, called estrogen receptor (ER)-positive and those that require the HER2 protein for growth, very few targeted therapies exist for the 10-15 percent of breast cancers that require neither steroid hormones nor HER2. These breast cancers, called triple-negative breast cancer are often aggressive with a high likelihood of spreading to other parts of the body—a process called metastasis. Dr. Brown’s group is using a CRISPR-screening technology to identify new drivers of TNBC that might be targeted in combination with standard therapies to improve outcomes for patients with this disease.

Current investigation: In his current study, he is focused on fibroblast growth factor receptor (FGFR), a potent signaling protein that is overactive in some cancers including some TNBC. His team is conducting studies to understand how FGFR acts to drive the growth of TNBC and identify strategies to therapeutically target it.

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Research area: Development of novel therapies for drug-resistant and aggressive breast cancers

Impact: While there are effective targeted therapies for breast cancer that are driven by estrogen, called estrogen receptor (ER)-positive and those that require the HER2 protein for growth, very few targeted therapies exist for the 10-15 percent of breast cancers that require neither steroid hormones nor HER2. These breast cancers, called triple-negative breast cancer are often aggressive with a high likelihood of spreading to other parts of the body—a process called metastasis. Dr. Brown’s group is using a CRISPR-screening technology to identify new drivers of TNBC that might be targeted in combination with standard therapies to improve outcomes for patients with this disease.

Current investigation: In his current study, he is focused on fibroblast growth factor receptor (FGFR), a potent signaling protein that is overactive in some cancers including some TNBC. His team is conducting studies to understand how FGFR acts to drive the growth of TNBC and identify strategies to therapeutically target it.

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I would not have been able to explore a new area of breast cancer research and would not have discovered a potential new combination therapy for women with breast cancer.

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Emil Frei III Professor of Medicine
Director, Center for Functional Cancer Epigenetics
Dana-Farber Cancer Institute

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If not for BCRF I would not have been able to explore a new area of breast cancer research and would not have discovered a potential new combination therapy for women with breast cancer. —Dr. Brown

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If not for BCRF I would not have been able to explore a new area of breast cancer research and would not have discovered a potential new combination therapy for women with breast cancer. —Dr. Brown

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Combatting drug resistance in triple-negative breast cancer through new strategies for combination therapies.

Impact

Triple negative breast cancer (TNBC) is an aggressive subtype, and while chemotherapy and immunotherapy are successful in some patients, many develop metastasis and succumb to their disease. This is partly due to the diversity of TNBC tumors—no single therapy will be appropriate for all TNBC patients. The overarching goal of Dr. Myles Brown’s work is to discover new treatments for TNBC by further stratifying tumors into new subtypes, which can in turn reveal new therapeutic targets. For example, some TNBC tumors may be driven by the gene FGFR, which can promote growth and metastatic spread. This suggests that patients with FGFR-positive tumors could be treated with an FGFR-targeted therapy, but clinical trials have been disappointing thus far due to drug resistance.

Progress Thus Far

The team is interested in learning why FGFR-positive TNBC tumors are resistant to FGFR-targeted therapy, and their work culminated in several exciting breakthroughs that were recently published in the journal, Nature Cell Biology. They discovered that high amounts of FGFR seen in some TNBC tumors alter the activity of several genes at once, reprogramming the cells in a way that cannot be treated by targeting a single gene. They further discovered that the activated genes contribute to a change in tumor cell metabolism, circumventing the cells’ dependence on FGFR, and making them resistant to FGFR-targeting therapies.

What’s Next

In the coming year the team will conduct molecular analysis in patient-derived tumors to confirm that their findings. In addition, they will explore the therapeutic potential of combining FGFR inhibitors with therapies that affect metabolism and the genetic reprogramming they encountered in FGFR-resistant cells.

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Combatting drug resistance in triple-negative breast cancer through new strategies for combination therapies.

Impact

Triple negative breast cancer (TNBC) is an aggressive subtype, and while chemotherapy and immunotherapy are successful in some patients, many develop metastasis and succumb to their disease. This is partly due to the diversity of TNBC tumors—no single therapy will be appropriate for all TNBC patients. The overarching goal of Dr. Myles Brown’s work is to discover new treatments for TNBC by further stratifying tumors into new subtypes, which can in turn reveal new therapeutic targets. For example, some TNBC tumors may be driven by the gene FGFR, which can promote growth and metastatic spread. This suggests that patients with FGFR-positive tumors could be treated with an FGFR-targeted therapy, but clinical trials have been disappointing thus far due to drug resistance.

Progress Thus Far

The team is interested in learning why FGFR-positive TNBC tumors are resistant to FGFR-targeted therapy, and their work culminated in several exciting breakthroughs that were recently published in the journal, Nature Cell Biology. They discovered that high amounts of FGFR seen in some TNBC tumors alter the activity of several genes at once, reprogramming the cells in a way that cannot be treated by targeting a single gene. They further discovered that the activated genes contribute to a change in tumor cell metabolism, circumventing the cells’ dependence on FGFR, and making them resistant to FGFR-targeting therapies.

What’s Next

In the coming year the team will conduct molecular analysis in patient-derived tumors to confirm that their findings. In addition, they will explore the therapeutic potential of combining FGFR inhibitors with therapies that affect metabolism and the genetic reprogramming they encountered in FGFR-resistant cells.

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Learn more about Powel H. Brown at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Powel H. Brown | Researcher | Breast Cancer Research Foundation

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Learn more about Powel H. Brown at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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John Charles Cain Distinguished Chair
Department of Clinical Cancer Prevention
University of Texas MD Anderson Cancer Center
Houston, Texas

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The University of Texas MD Anderson Cancer Center

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Powel Brown is a physician-scientist and molecular biology researcher focused on identifying novel strategies to effectively treat breast cancer at the University of Texas, MD Anderson Cancer Center, where he is Chair of the Department of Clinical Cancer Prevention. He is currently identifying molecules highly expressed in triple-negative breast cancer that are essential for growth, survival, and metastasis, and developing strategies to inhibit these molecules for the treatment of this aggressive form of breast cancer. Dr.

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Powel Brown is a physician-scientist and molecular biology researcher focused on identifying novel strategies to effectively treat breast cancer at the University of Texas, MD Anderson Cancer Center, where he is Chair of the Department of Clinical Cancer Prevention. He is currently identifying molecules highly expressed in triple-negative breast cancer that are essential for growth, survival, and metastasis, and developing strategies to inhibit these molecules for the treatment of this aggressive form of breast cancer. Dr. Brown has previously used genomic techniques to identify distinct subtypes of TNBC with varying clinical outcomes (1), and have also identified specific kinases (2), phosphatases (3), and transcription factors (4) critical for the growth and survival of TNBC. Through his study of highly expressed and activated transcription factors in TNBC, he discovered that SOX transcription factors are essential for TNBC survival and metastasis. These results provided the rationale to target Sox9 for the prevention and treatment of breast cancer metastasis. 

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Powel Brown is a physician-scientist and molecular biology researcher focused on identifying novel strategies to effectively treat breast cancer at the University of Texas, MD Anderson Cancer Center, where he is Chair of the Department of Clinical Cancer Prevention. He is currently identifying molecules highly expressed in triple-negative breast cancer that are essential for growth, survival, and metastasis, and developing strategies to inhibit these molecules for the treatment of this aggressive form of breast cancer. Dr. Brown has previously used genomic techniques to identify distinct subtypes of TNBC with varying clinical outcomes (1), and have also identified specific kinases (2), phosphatases (3), and transcription factors (4) critical for the growth and survival of TNBC. Through his study of highly expressed and activated transcription factors in TNBC, he discovered that SOX transcription factors are essential for TNBC survival and metastasis. These results provided the rationale to target Sox9 for the prevention and treatment of breast cancer metastasis.

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Goal: To identify new targets for the treatment and prevention of triple negative breast cancer (TNBC).

Impact: Dr. Brown aims to understand how genes that are essential for the survival of TNBC are regulated and how to effectively block them. Ultimately, his work could pave the way for novel therapeutic strategies for TNBC.

What’s next: He and his team are targeting proteins that regulate genes critical to TNBC survival with small molecule inhibitors. These could have the potential to become drugs for the treatment and prevention of breast cancer metastases.

TNBC is an aggressive form of breast cancer with a high likelihood of spreading to other tissues. There are few treatment options for these patients beyond chemotherapy, since TNBC lacks receptors that respond to hormone-based therapies. Dr. Brown is conducting laboratory experiments that will inform the development of new therapeutic strategies to treat or prevent the spread of TNBC.

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Goal: To identify new targets for the treatment and prevention of triple negative breast cancer (TNBC).

Impact: Dr. Brown aims to understand how genes that are essential for the survival of TNBC are regulated and how to effectively block them. Ultimately, his work could pave the way for novel therapeutic strategies for TNBC.

What’s next: He and his team are targeting proteins that regulate genes critical to TNBC survival with small molecule inhibitors. These could have the potential to become drugs for the treatment and prevention of breast cancer metastases.

TNBC is an aggressive form of breast cancer with a high likelihood of spreading to other tissues. There are few treatment options for these patients beyond chemotherapy, since TNBC lacks receptors that respond to hormone-based therapies. Dr. Brown is conducting laboratory experiments that will inform the development of new therapeutic strategies to treat or prevent the spread of TNBC.

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Research area: Developing novel therapeutic targets for the treatment of triple negative breast cancer (TNBC), an aggressive form of the disease with a high likelihood of spreading to other tissues.

Impact: TNBC is difficult to treat because the tumors lack the estrogen, progesterone, and HER-2 receptors that are the target of the most common and effective forms of therapy. Dr. Brown is studying transcription factors—molecules that turn genes on or off—that could be targeted for drug development to prevent or treat the spread of TNBC.

Current investigation: He and his team are studying a protein called SOX9, which they found to be a “master regulator” of TNBC survival and metastasis. It controls the expression of genes that determine whether cancer cells invade through tissue and spread.

What he’s learned so far: Dr. Brown has shown that inhibition of SOX9 stops progression of metastatic disease in laboratory studies. He and his team have identified activators of SOX9 and genes regulated by SOX9.

What’s next: He and his team are targeting protein activators of SOX9 with small molecule inhibitors to block SOX9 activity and slow or prevent TNBC metastasis in the laboratory.

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Research area: Developing novel therapeutic targets for the treatment of triple negative breast cancer (TNBC), an aggressive form of the disease with a high likelihood of spreading to other tissues.

Impact: TNBC is difficult to treat because the tumors lack the estrogen, progesterone, and HER-2 receptors that are the target of the most common and effective forms of therapy. Dr. Brown is studying transcription factors—molecules that turn genes on or off—that could be targeted for drug development to prevent or treat the spread of TNBC.

Current investigation: He and his team are studying a protein called SOX9, which they found to be a “master regulator” of TNBC survival and metastasis. It controls the expression of genes that determine whether cancer cells invade through tissue and spread.

What he’s learned so far: Dr. Brown has shown that inhibition of SOX9 stops progression of metastatic disease in laboratory studies. He and his team have identified activators of SOX9 and genes regulated by SOX9.

What’s next: He and his team are targeting protein activators of SOX9 with small molecule inhibitors to block SOX9 activity and slow or prevent TNBC metastasis in the laboratory.

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John Charles Cain Distinguished Chair
Department of Clinical Cancer Prevention
University of Texas MD Anderson Cancer Center
Houston, Texas

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Identifying new targets for the treatment and prevention of triple-negative breast cancer.

Impact

Triple-negative breast cancers (TNBC) are the most aggressive form of breast cancer, have a very poor prognosis, and patients with TNBC have few treatment options. More strategies to combat TNBC are urgently needed. Dr. Brown’s goal is to identify more effective and safe targeted therapies for patients with TNBC.

Progress Thus Far

Dr. Brown’s previous BCRF-funded work demonstrated that a protein called SOX9, suppresses cell death and is essential for the survival and growth of TNBC. However, the SOX9 protein is difficult to target in the clinical setting. To address this problem, Dr. Brown and his team have identified other proteins that interact with and likely control SOX9 activity in TNBC. The team recently identified a potential target protein that interacts with SOX9 to control cell growth and metastasis.

What's next

In the next year, Dr. Brown’s work will focus on developing effective and well-tolerated targeted therapies for the prevention of BRCA1-driven breast cancer. The findings from this preclinical study may demonstrate the anti-tumor immune effects of targeted therapies responsible for the suppression of BRCA1 breast tumor formation. He hopes to identify key immune cells and novel immune targets important for the development of tumors with BRCA1 mutations that can ultimately lead to the effective prevention of this aggressive form of breast cancer.

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Identifying new targets for the treatment and prevention of triple-negative breast cancer.

Impact

Triple-negative breast cancers (TNBC) are the most aggressive form of breast cancer, have a very poor prognosis, and patients with TNBC have few treatment options. More strategies to combat TNBC are urgently needed. Dr. Brown’s goal is to identify more effective and safe targeted therapies for patients with TNBC.

Progress Thus Far

Dr. Brown’s previous BCRF-funded work demonstrated that a protein called SOX9, suppresses cell death and is essential for the survival and growth of TNBC. However, the SOX9 protein is difficult to target in the clinical setting. To address this problem, Dr. Brown and his team have identified other proteins that interact with and likely control SOX9 activity in TNBC. The team recently identified a potential target protein that interacts with SOX9 to control cell growth and metastasis.

What's next

In the next year, Dr. Brown’s work will focus on developing effective and well-tolerated targeted therapies for the prevention of BRCA1-driven breast cancer. The findings from this preclinical study may demonstrate the anti-tumor immune effects of targeted therapies responsible for the suppression of BRCA1 breast tumor formation. He hopes to identify key immune cells and novel immune targets important for the development of tumors with BRCA1 mutations that can ultimately lead to the effective prevention of this aggressive form of breast cancer.

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Learn more about Lewis C. Cantley at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Lewis C. Cantley | Researcher | Breast Cancer Research Foundation

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Learn more about Lewis C. Cantley at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor of Cell Biology, Harvard Medical School

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Lewis C. Cantley, PhD, is a professor of cell biology at Harvard Medical School. Prior to this appointment, he was the Margaret and Herman Sokol Professor and Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College/Ronald P. Stanton Clinical Cancer Program at New York Presbyterian Hospital (2012-22). Dr.

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Lewis C. Cantley, PhD, is a professor of cell biology at Harvard Medical School. Prior to this appointment, he was the Margaret and Herman Sokol Professor and Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College/Ronald P. Stanton Clinical Cancer Program at New York Presbyterian Hospital (2012-22). Dr. Cantley is a graduate of West Virginia Wesleyan College, obtained a PhD in biophysical chemistry from Cornell University, completed postdoctoral training at Harvard University, and subsequently taught and conducted research in biochemistry, physiology and cancer biology at Beth Israel Deaconess Medical Center and Harvard Medical School. His laboratory discovered the PI 3-Kinase pathway that plays a critical role in insulin signaling and in cancers.

Dr. Cantley was elected to the National Academy of Inventors in 2020, the Institute of Medicine in 2014, the National Academy of Sciences in 2001, and the American Academy of Arts and Sciences in 1999. Among his other awards are the ASBMB Avanti Award for Lipid Research in 1998, the Heinrich Wieland Preis for Lipid Research in 2000, the Caledonian Prize from the Royal Society of Edinburgh in 2002, the 2005 Pezcoller Foundation–AACR International Award for Cancer Research, the 2009 Rolf Luft Award for Diabetes and Endocrinology Research from the Karolinska Institute, Stockholm, the 2011 Pasrow Prize for Cancer Research, the 2013 Breakthrough in Life Sciences Prize and the 2013 Jacobaeus Prize for Diabetes Research from the Karolinska Institute and the 2015 AACR Princess Takamatsu Memorial Lectureship.

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Lewis C. Cantley, PhD, is a professor of cell biology at Harvard Medical School. Prior to this appointment, he was the Margaret and Herman Sokol Professor and Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College/Ronald P. Stanton Clinical Cancer Program at New York Presbyterian Hospital (2012-22). Dr. Cantley is a graduate of West Virginia Wesleyan College, obtained a PhD in biophysical chemistry from Cornell University, completed postdoctoral training at Harvard University, and subsequently taught and conducted research in biochemistry, physiology and cancer biology at Beth Israel Deaconess Medical Center and Harvard Medical School. His laboratory discovered the PI 3-Kinase pathway that plays a critical role in insulin signaling and in cancers.

Dr. Cantley was elected to the National Academy of Inventors in 2020, the Institute of Medicine in 2014, the National Academy of Sciences in 2001, and the American Academy of Arts and Sciences in 1999. Among his other awards are the ASBMB Avanti Award for Lipid Research in 1998, the Heinrich Wieland Preis for Lipid Research in 2000, the Caledonian Prize from the Royal Society of Edinburgh in 2002, the 2005 Pezcoller Foundation–AACR International Award for Cancer Research, the 2009 Rolf Luft Award for Diabetes and Endocrinology Research from the Karolinska Institute, Stockholm, the 2011 Pasrow Prize for Cancer Research, the 2013 Breakthrough in Life Sciences Prize and the 2013 Jacobaeus Prize for Diabetes Research from the Karolinska Institute and the 2015 AACR Princess Takamatsu Memorial Lectureship.

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Research area: Understanding how cellular signals alter breast cancer growth and response to therapy and identifying ways to enhance the effectiveness of targeted cancer therapies.

Impact: Dr. Cantley was the first to discover PI3K, a protein controlled by PIK3CA, the most frequently mutated gene in breast cancer. Recently, the P13K inhibitor, alpelisib, has been approved for treating metastatic breast cancer but its effectiveness has been limited, because tumor cells can activate other growth pathways to counter the effects of alpelisib. Dr. Cantley is studying the mechanism of resistance to these drugs in order to develop new ways to improve treatment outcomes for metastatic breast cancer patients.

Progress Thus Far: To understand the role of these protein kinases in breast cancer growth and metastasis, Dr. Cantley and his colleagues have engineered laboratory models of breast cancer brain metastases.  Through utilization of these models, they have discovered two separate protein kinases that can directly modify PI3K. In addition, the team has identified a specific site on the P13K protein that can be targeted to inhibit P13K signaling. This finding may help identify new ways to target PI3K to treat metastatic breast cancer.

What’s next: In addition to their ongoing studies, Dr. Cantley and his team will also pursue a new line of investigation into tumors with BRCA1 mutations (the most common mutation found in hereditary breast cancers) and other aggressive and hard-to-treat tumors. They will investigate whether high doses of the B-vitamin, folate, and vitamin C can be used to selectively kill BRCA1-deficient breast cancer cells. This line of research is inspired by the discovery that folate can generate formaldehyde, a toxin that promotes cell death in BRCA1-deficient cells, and the discovery that vitamin C can kill cancer cells by triggering the accumulation of other toxins.

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Research area: Understanding how cellular signals alter breast cancer growth and response to therapy and identifying ways to enhance the effectiveness of targeted cancer therapies.

Impact: Dr. Cantley was the first to discover PI3K, a protein controlled by PIK3CA, the most frequently mutated gene in breast cancer. Recently, the P13K inhibitor, alpelisib, has been approved for treating metastatic breast cancer but its effectiveness has been limited, because tumor cells can activate other growth pathways to counter the effects of alpelisib. Dr. Cantley is studying the mechanism of resistance to these drugs in order to develop new ways to improve treatment outcomes for metastatic breast cancer patients.

Progress Thus Far: To understand the role of these protein kinases in breast cancer growth and metastasis, Dr. Cantley and his colleagues have engineered laboratory models of breast cancer brain metastases.  Through utilization of these models, they have discovered two separate protein kinases that can directly modify PI3K. In addition, the team has identified a specific site on the P13K protein that can be targeted to inhibit P13K signaling. This finding may help identify new ways to target PI3K to treat metastatic breast cancer.

What’s next: In addition to their ongoing studies, Dr. Cantley and his team will also pursue a new line of investigation into tumors with BRCA1 mutations (the most common mutation found in hereditary breast cancers) and other aggressive and hard-to-treat tumors. They will investigate whether high doses of the B-vitamin, folate, and vitamin C can be used to selectively kill BRCA1-deficient breast cancer cells. This line of research is inspired by the discovery that folate can generate formaldehyde, a toxin that promotes cell death in BRCA1-deficient cells, and the discovery that vitamin C can kill cancer cells by triggering the accumulation of other toxins.

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Research area: Understanding how cellular machines called protein kinases affect breast cancer growth to identify ways to enhance the effectiveness of targeted cancer therapies.

Impact: Dr. Cantley was the first to discover a protein called PI3K which is the most frequently mutated protein known to cause breast cancer. Recently, the PI3K inhibitor alpelisib has been approved for the treatment of metastatic breast cancer. However, patients can have limited responses to P13K-inhibitor or develop resistance — this necessitates the development of rational new treatment strategies. Dr. Cantley is determining new methods to target P13K to develop novel combinations of therapies to treat metastatic breast cancer.

Current investigation: Dr. Cantley is examining the protein phosphorylation of PI3K and its downstream function in breast cancer models to identify novel therapeutic strategies for breast cancer patients.

What he’s learned so far: He has discovered two separate protein kinases that can directly modify PI3K, turning PI3K off or on. To understand the role of these protein kinases in breast cancer growth and metastasis, Dr. Cantley and his colleagues have engineered breast cancer laboratory models of brain metastases.

What’s next: He and his team will continue to investigate the PI3K pathway by focusing on the phospho-regulation of PI3K by protein kinases and the role it plays in breast cancer growth and responses to therapy. They will utilize patient-derived breast cancer cells grown in culture and in three-dimension to identify novel combination therapies with PI3K inhibitors for treatment of metastatic breast cancer.

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Research area: Understanding how cellular machines called protein kinases affect breast cancer growth to identify ways to enhance the effectiveness of targeted cancer therapies.

Impact: Dr. Cantley was the first to discover a protein called PI3K which is the most frequently mutated protein known to cause breast cancer. Recently, the PI3K inhibitor alpelisib has been approved for the treatment of metastatic breast cancer. However, patients can have limited responses to P13K-inhibitor or develop resistance — this necessitates the development of rational new treatment strategies. Dr. Cantley is determining new methods to target P13K to develop novel combinations of therapies to treat metastatic breast cancer.

Current investigation: Dr. Cantley is examining the protein phosphorylation of PI3K and its downstream function in breast cancer models to identify novel therapeutic strategies for breast cancer patients.

What he’s learned so far: He has discovered two separate protein kinases that can directly modify PI3K, turning PI3K off or on. To understand the role of these protein kinases in breast cancer growth and metastasis, Dr. Cantley and his colleagues have engineered breast cancer laboratory models of brain metastases.

What’s next: He and his team will continue to investigate the PI3K pathway by focusing on the phospho-regulation of PI3K by protein kinases and the role it plays in breast cancer growth and responses to therapy. They will utilize patient-derived breast cancer cells grown in culture and in three-dimension to identify novel combination therapies with PI3K inhibitors for treatment of metastatic breast cancer.

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Professor of Cell Biology, Harvard Medical School 

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Understanding how cellular signals alter breast cancer growth and response to therapy and identifying ways to enhance the effectiveness of targeted cancer therapies.

Impact

Dr. Cantley was the first to discover PI3K, a protein controlled by PIK3CA, the most frequently mutated gene in breast cancer. The P13K inhibitor, alpelisib, has been approved for treating metastatic breast cancer but its effectiveness has been limited because tumor cells can activate other growth pathways to counter its effects. Dr. Cantley’s group has focused on the role of the PI3K in breast cancer growth and metastasis. His group has identified proteins that can modify [the function of] PI3K as well as ways to target the protein to block PI3K activity.  This finding may help identify new ways to target PI3K to treat metastatic breast cancer. In other studies, Dr. Cantley has focused on developing a novel therapeutic strategy for the treatment of breast cancers with BRCA mutations, which are often particularly aggressive and hard-to-treat. Taken together, Dr. Cantley’s research have the potential to develop novel ways to improve treatment outcomes for metastatic breast cancer patients.

Progress Thus Far

Studies have shown that high doses of two vitamins can generate metabolic toxins specifically in BRCA1-mutant cancer cells.  Dr. Cantley showed that these two vitamins work together to kill BRCA1- and BRCA2-defective cancer cells by generating reactive oxygen species, which are toxic to the cells. Building on these findings, the team designed preclinical studies to assess the therapeutic efficacy of combining these two vitamins.

What’s next

Dr. Cantley and his team will continue to test the efficacy of the vitamin combination in laboratory models. One target of interest is a protein responsible for transporting one of the two vitamins, which is commonly overexpressed in breast cancers. The team will examine the role of this transporter in the toxicity of the vitamin combination in BRCA1-defective cells. These studies may provide insight into new treatments for BRCA1-associated breast cancers.

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Understanding how cellular signals alter breast cancer growth and response to therapy and identifying ways to enhance the effectiveness of targeted cancer therapies.

Impact

Dr. Cantley was the first to discover PI3K, a protein controlled by PIK3CA, the most frequently mutated gene in breast cancer. The P13K inhibitor, alpelisib, has been approved for treating metastatic breast cancer but its effectiveness has been limited because tumor cells can activate other growth pathways to counter its effects. Dr. Cantley’s group has focused on the role of the PI3K in breast cancer growth and metastasis. His group has identified proteins that can modify [the function of] PI3K as well as ways to target the protein to block PI3K activity.  This finding may help identify new ways to target PI3K to treat metastatic breast cancer. In other studies, Dr. Cantley has focused on developing a novel therapeutic strategy for the treatment of breast cancers with BRCA mutations, which are often particularly aggressive and hard-to-treat. Taken together, Dr. Cantley’s research have the potential to develop novel ways to improve treatment outcomes for metastatic breast cancer patients.

Progress Thus Far

Studies have shown that high doses of two vitamins can generate metabolic toxins specifically in BRCA1-mutant cancer cells.  Dr. Cantley showed that these two vitamins work together to kill BRCA1- and BRCA2-defective cancer cells by generating reactive oxygen species, which are toxic to the cells. Building on these findings, the team designed preclinical studies to assess the therapeutic efficacy of combining these two vitamins.

What’s next

Dr. Cantley and his team will continue to test the efficacy of the vitamin combination in laboratory models. One target of interest is a protein responsible for transporting one of the two vitamins, which is commonly overexpressed in breast cancers. The team will examine the role of this transporter in the toxicity of the vitamin combination in BRCA1-defective cells. These studies may provide insight into new treatments for BRCA1-associated breast cancers.

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Learn more about Lisa A. Carey at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Lisa A. Carey | Researcher | Breast Cancer Research Foundation

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Learn more about Lisa A. Carey at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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L. Richardson and Marilyn Jacob Preyer Distinguished Professor in Breast Cancer Research
Deputy Director of Clinical Sciences, Lineberger Comprehensive Cancer Center
University of North Carolina
Chapel Hill, North Carolina

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Lisa A. Carey, MD is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the Department of Medicine at the University of North Carolina (UNC). She graduated from Wellesley College, then received her medical degree from the Johns Hopkins University School of Medicine where she remained for her residency in Internal Medicine followed by a fellowship in Medical Oncology and an advanced degree in Clinical Investigations. Dr. Carey joined the UNC faculty and Lineberger Comprehensive Cancer Center in 1998.

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Lisa A. Carey, MD is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the Department of Medicine at the University of North Carolina (UNC). She graduated from Wellesley College, then received her medical degree from the Johns Hopkins University School of Medicine where she remained for her residency in Internal Medicine followed by a fellowship in Medical Oncology and an advanced degree in Clinical Investigations. Dr. Carey joined the UNC faculty and Lineberger Comprehensive Cancer Center in 1998. She was the Chief of the Division of Hematology and Oncology and Physician-in-Chief of the North Carolina Cancer Hospital from 2012-2020.  In 2020, Dr. Carey assumed the role of Deputy Director of Clinical Sciences at Lineberger Comprehensive Cancer Center.  

Dr. Carey has a longstanding research interest in the clinical application of laboratory findings in breast cancer, with a particular interest in the clinical implications of different molecular subtypes of breast cancer. She designs and leads clinical trials of novel drugs and approaches, and is a close collaborator with several laboratory investigators and epidemiologists. Dr. Carey has served in many roles for the American Society of Clinical Oncology (ASCO), the American Association for Cancer Research (AACR) and the NCI.  She is a member of the Johns Hopkins Society of Scholars, the recipient of the NCI Director’s Service Award, and honored to be a Fellow of the American Society of Clinical Oncology (FASCO).  Dr. Carey serves as the co-chair of the Alliance National Cooperative Group Breast Committee since 2016.


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Lisa A. Carey, MD is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the Department of Medicine at the University of North Carolina (UNC). She graduated from Wellesley College, then received her medical degree from the Johns Hopkins University School of Medicine where she remained for her residency in Internal Medicine followed by a fellowship in Medical Oncology and an advanced degree in Clinical Investigations. Dr. Carey joined the UNC faculty and Lineberger Comprehensive Cancer Center in 1998. She was the Chief of the Division of Hematology and Oncology and Physician-in-Chief of the North Carolina Cancer Hospital from 2012-2020. In 2020, Dr. Carey assumed the role of Deputy Director of Clinical Sciences at Lineberger Comprehensive Cancer Center.

Dr. Carey has a longstanding research interest in the clinical application of laboratory findings in breast cancer, with a particular interest in the clinical implications of different molecular subtypes of breast cancer. She designs and leads clinical trials of novel drugs and approaches, and is a close collaborator with several laboratory investigators and epidemiologists. Dr. Carey has served in many roles for the American Society of Clinical Oncology (ASCO), the American Association for Cancer Research (AACR) and the NCI. She is a member of the Johns Hopkins Society of Scholars, the recipient of the NCI Director’s Service Award, and honored to be a Fellow of the American Society of Clinical Oncology (FASCO). Dr. Carey serves as the co-chair of the Alliance National Cooperative Group Breast Committee since 2016.

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Research Area: Understanding the evolution of breast cancer metastasis to improve therapeutic strategies and identify new drug targets.

Impact: There is no cure for metastatic breast cancer (MBC)—cancer that has spread from the breast to distant organs. Most of our knowledge about breast cancer comes from studying tumors in the breast, not their metastases in other sites, but there can be important changes after spread that affect treatment outcomes. Dr. Lisa Carey and her team address this by comparing primary breast tumors with metastases, performing cellular and genetic analyses to reveal their differences. They are particularly interested in organ tropism: why different subtypes of breast cancer tend to metastasize to specific organs. For example, ER-positive breast cancers often metastasize to bone, whereas ER-negative and HER2-positive breast cancers typically spread to major internal organs. Dr. Carey’s team also studies de novo MBC—cancer that has already spread by the time it is diagnosed. These patients live longer than those with recurrent MBC (when cancer spreads after treatment), which reveals potential differences in the biology of their tumors. Their research could help inform therapeutic strategies for recurrent versus de novo MBC.

Progress Thus Far: The team recently examined molecular disparities between de novo and recurrent MBC, uncovering a propensity for specific breast cancer subtypes: de novo is more likely to be HER2-positive, and less likely to be triple-negative. Dr. Carey’s team also explored metastatic organ tropism and found a molecular signature in ER-positive patients that predicts metastasis to the lung, liver, and brain. The genes associated with this signature could inform the development of new therapies.

What’s Next: Dr. Carey’s team will continue exploring the biology of de novo metastatic breast cancer, observing if prolonged survival seen in these patients is explained by differences in the immune system’s response. They will also assess the performance of genetic prognostic tests on metastatic tissue samples when compared to breast tumors—looking for discrepancies in results, as that could reveal two different therapeutic strategies for a patient. Their findings may initiate a larger clinical trial to test the use of prognostic assays for therapeutic decision making in metastatic breast cancer.

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Research Area: Understanding the evolution of breast cancer metastasis to improve therapeutic strategies and identify new drug targets.

Impact: There is no cure for metastatic breast cancer (MBC)—cancer that has spread from the breast to distant organs. Most of our knowledge about breast cancer comes from studying tumors in the breast, not their metastases in other sites, but there can be important changes after spread that affect treatment outcomes. Dr. Lisa Carey and her team address this by comparing primary breast tumors with metastases, performing cellular and genetic analyses to reveal their differences. They are particularly interested in organ tropism: why different subtypes of breast cancer tend to metastasize to specific organs. For example, ER-positive breast cancers often metastasize to bone, whereas ER-negative and HER2-positive breast cancers typically spread to major internal organs. Dr. Carey’s team also studies de novo MBC—cancer that has already spread by the time it is diagnosed. These patients live longer than those with recurrent MBC (when cancer spreads after treatment), which reveals potential differences in the biology of their tumors. Their research could help inform therapeutic strategies for recurrent versus de novo MBC.

Progress Thus Far: The team recently examined molecular disparities between de novo and recurrent MBC, uncovering a propensity for specific breast cancer subtypes: de novo is more likely to be HER2-positive, and less likely to be triple-negative. Dr. Carey’s team also explored metastatic organ tropism and found a molecular signature in ER-positive patients that predicts metastasis to the lung, liver, and brain. The genes associated with this signature could inform the development of new therapies.

What’s Next: Dr. Carey’s team will continue exploring the biology of de novo metastatic breast cancer, observing if prolonged survival seen in these patients is explained by differences in the immune system’s response. They will also assess the performance of genetic prognostic tests on metastatic tissue samples when compared to breast tumors—looking for discrepancies in results, as that could reveal two different therapeutic strategies for a patient. Their findings may initiate a larger clinical trial to test the use of prognostic assays for therapeutic decision making in metastatic breast cancer.

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Research area: Understanding how different tumors respond to treatment and how tumors that have spread to other tissues vary from the original tumor.

Impact: Understanding how cancer spreads will help inform future clinical trials to treat and potentially cure metastatic breast cancer, but studying MBC is inherently difficult as tumors are smaller and often inaccessible. Even when operable, surgery to remove a metastatic tumor for research purposes is unethical as it does not provide a survival benefit to the patient and could cause harm. Dr. Carey is able to utilize samples obtained during rapid autopsy and clinical trials to study a variety of MBC tumor types to examine how breast cancer spreads from the original breast tumor to distant organs.

Current Investigation: Dr. Carey will look at the unique differences between de novo metastases—those that were present at diagnosis—versus those that developed later, often many years after treatment for the primary cancer ended, to discern differences in tumor biology. By studying the similarities and differences between the original breast cancer and metastatic tumors she hopes to identify unique markers that may help in the development of personalized treatment for all breast cancer patients.

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Research area: Understanding how different tumors respond to treatment and how tumors that have spread to other tissues vary from the original tumor.

Impact: Understanding how cancer spreads will help inform future clinical trials to treat and potentially cure metastatic breast cancer, but studying MBC is inherently difficult as tumors are smaller and often inaccessible. Even when operable, surgery to remove a metastatic tumor for research purposes is unethical as it does not provide a survival benefit to the patient and could cause harm. Dr. Carey is able to utilize samples obtained during rapid autopsy and clinical trials to study a variety of MBC tumor types to examine how breast cancer spreads from the original breast tumor to distant organs.

Current Investigation: Dr. Carey will look at the unique differences between de novo metastases—those that were present at diagnosis—versus those that developed later, often many years after treatment for the primary cancer ended, to discern differences in tumor biology. By studying the similarities and differences between the original breast cancer and metastatic tumors she hopes to identify unique markers that may help in the development of personalized treatment for all breast cancer patients.

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L. Richardson and Marilyn Jacob Preyer Distinguished Professor in Breast Cancer Research
Deputy Director of Clinical Sciences, Lineberger Comprehensive Cancer Center
University of North Carolina
Chapel Hill, North Carolina

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“Most of our knowledge comes from studying the original cancer, not the metastatic cancer, and it’s increasingly clear that there are important differences after cancer spreads that may be important in improving treatment.” – Dr. Carey

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“Most of our knowledge comes from studying the original cancer, not the metastatic cancer, and it’s increasingly clear that there are important differences after cancer spreads that may be important in improving treatment.” – Dr. Carey

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Understanding the evolution of breast cancer metastasis to improve therapeutic strategies and identify new drug targets.

Impact

There is no cure for metastatic breast cancer (MBC)—cancer that has spread from the breast to distant organs. Most of our knowledge about breast cancer comes from studying tumors in the breast, not their metastases in other sites, but there can be important changes after spread that affect treatment outcomes. Dr. Lisa Carey and her team address this by comparing primary breast tumors with metastases, performing cellular and genetic analyses to reveal their differences. Dr. Carey’s team also studies de novo MBC, which is cancer that has already spread by the time it is diagnosed. Several datasets suggest that de novo disease—which represents almost 30 percent of metastatic breast cancers—is associated with substantially longer survival when compared to recurrent metastasis (when cancer spreads after treatment), but it is still incurable. Dr. Carey and her team will analyze samples from de novo metastasis to help design therapeutic strategies for these patients, who may require care that differs from the standard practice for recurrent metastasis.

Progress Thus Far

In the last year, Dr. Carey and her team tested the performance of genetic prognostic tests in metastatic breast cancer to help guide treatment decisions. Typically, these assays are performed on tissue from the original (primary) breast tumor. Dr. Carey’s team explored whether the results of these tests differed when using samples from metastases. They found that there were variations between that tests that reflected the unique environments of each metastatic site. The results of this may affect how these prognostic assays are used for therapeutic decision making in metastatic breast cancer. In addition, the team continued their exploration of de novo metastasis, assessing their 1,000-patient metastatic cancer database with clinical information for 232 patients with de novo disease. They confirmed that de novo breast cancer has a better prognosis, independent of other contributing factors including treatment type and clinical subtype. This raises important biological questions—why do breast cancer patients who experience recurrent metastasis fare worse than de novo metastasis patients? They will continue to explore this question as more information may shape how breast cancer is treated, especially breast cancers that are likely to spread.

What’s Next

In the coming year, the team will continue their efforts to clarify the biologic changes that occur during metastasis, and to characterize variations in molecular profiles across multiple metastatic organ sites. They will also proceed with studies in conjunction with the HARMONY study, an ongoing clinical trial in which patients with newly diagnosed metastatic breast cancer undergo diagnostic testing. Their research will continue to explore the differences between diagnostic results for primary breast tumors and metastatic tumors, as this affects treatment decision-making. This trial has accrued over 200 of the planned 500 patients.

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Understanding the evolution of breast cancer metastasis to improve therapeutic strategies and identify new drug targets.

Impact

There is no cure for metastatic breast cancer (MBC)—cancer that has spread from the breast to distant organs. Most of our knowledge about breast cancer comes from studying tumors in the breast, not their metastases in other sites, but there can be important changes after spread that affect treatment outcomes. Dr. Lisa Carey and her team address this by comparing primary breast tumors with metastases, performing cellular and genetic analyses to reveal their differences. Dr. Carey’s team also studies de novo MBC, which is cancer that has already spread by the time it is diagnosed. Several datasets suggest that de novo disease—which represents almost 30 percent of metastatic breast cancers—is associated with substantially longer survival when compared to recurrent metastasis (when cancer spreads after treatment), but it is still incurable. Dr. Carey and her team will analyze samples from de novo metastasis to help design therapeutic strategies for these patients, who may require care that differs from the standard practice for recurrent metastasis.

Progress Thus Far

In the last year, Dr. Carey and her team tested the performance of genetic prognostic tests in metastatic breast cancer to help guide treatment decisions. Typically, these assays are performed on tissue from the original (primary) breast tumor. Dr. Carey’s team explored whether the results of these tests differed when using samples from metastases. They found that there were variations between that tests that reflected the unique environments of each metastatic site. The results of this may affect how these prognostic assays are used for therapeutic decision making in metastatic breast cancer. In addition, the team continued their exploration of de novo metastasis, assessing their 1,000-patient metastatic cancer database with clinical information for 232 patients with de novo disease. They confirmed that de novo breast cancer has a better prognosis, independent of other contributing factors including treatment type and clinical subtype. This raises important biological questions—why do breast cancer patients who experience recurrent metastasis fare worse than de novo metastasis patients? They will continue to explore this question as more information may shape how breast cancer is treated, especially breast cancers that are likely to spread.

What’s Next

In the coming year, the team will continue their efforts to clarify the biologic changes that occur during metastasis, and to characterize variations in molecular profiles across multiple metastatic organ sites. They will also proceed with studies in conjunction with the HARMONY study, an ongoing clinical trial in which patients with newly diagnosed metastatic breast cancer undergo diagnostic testing. Their research will continue to explore the differences between diagnostic results for primary breast tumors and metastatic tumors, as this affects treatment decision-making. This trial has accrued over 200 of the planned 500 patients.

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Learn more about Jenny C. Chang at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Jenny C. Chang | Researcher | Breast Cancer Research Foundation

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Learn more about Jenny C. Chang at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Director, Methodist Cancer Center
Professor, Weill Cornell Medical College
Professor and Emily Herrmann Chair in Cancer Research, Houston Methodist Hospital

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The Methodist Hospital Research Institute

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Jenny C. Chang, MD obtained medical degree from Cambridge University, England and completed fellowship in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research. She was awarded research doctorate from the University of London. Breast cancer has been the focus of her research. She plans to improve the outcome of breast cancer patients by translating scientific discoveries directly into clinical practice and therapeutics.

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Jenny C. Chang, MD obtained medical degree from Cambridge University, England and completed fellowship in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research. She was awarded research doctorate from the University of London. Breast cancer has been the focus of her research. She plans to improve the outcome of breast cancer patients by translating scientific discoveries directly into clinical practice and therapeutics. To this end, her most recent work has centered on identifying the mechanisms by which breast cancer stem cells survive chemotherapy, radiation, and hormonal therapy, leading to recurrences, relapses, and metastasis. Her recent work has focused on the intrinsic therapy resistance of cancer stem cells, resulting in several publications and international presentations. In addition, she holds several federal grants evaluating novel biologic agents and patents on new technological advances, especially in the area of high throughput molecular profiling.

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Jenny C. Chang, MD obtained medical degree from Cambridge University, England and completed fellowship in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research. She was awarded research doctorate from the University of London. Breast cancer has been the focus of her research. She plans to improve the outcome of breast cancer patients by translating scientific discoveries directly into clinical practice and therapeutics. To this end, her most recent work has centered on identifying the mechanisms by which breast cancer stem cells survive chemotherapy, radiation, and hormonal therapy, leading to recurrences, relapses, and metastasis. Her recent work has focused on the intrinsic therapy resistance of cancer stem cells, resulting in several publications and international presentations. In addition, she holds several federal grants evaluating novel biologic agents and patents on new technological advances, especially in the area of high throughput molecular profiling.

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Research Area: To identify and test potential drug targets for the treatment of triple-negative breast cancer.

Impact: Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate remains low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for TNBC patients, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Progress Thus Far: Using previously developed state-of-the-art TNBC laboratory models, Dr. Chang and her team have shown that targeting interleukin 12 (IL12), a component of the tumor microenvironment, can make tumors more responsive to immunotherapies. In other studies, she and her colleagues have discovered a novel drug, L-NMMA, that targets a molecule known to promote tumor growth and metastasis. They are evaluating the efficacy of combining L-NMMA with another targeted drug, alpelisib (PIQRAY®) to treat TNBC. Preliminary studies indicate that this combination plus chemotherapy is an effective therapeutic approach to treat metaplastic breast cancer, the most aggressive subtype of TNBC.

What’s next: She and her team will continue to study the role of IL12 in response to immunotherapy to identify strategies to improve immunotherapy treatment for patients with TNBC. Also, Dr. Chang will continue to investigate the use of L-NMMA in combination with alpelisib and hopes to develop and conduct preclinical studies that will move to clinical evaluation in the near future.

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Research Area: To identify and test potential drug targets for the treatment of triple-negative breast cancer.

Impact: Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate remains low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for TNBC patients, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Progress Thus Far: Using previously developed state-of-the-art TNBC laboratory models, Dr. Chang and her team have shown that targeting interleukin 12 (IL12), a component of the tumor microenvironment, can make tumors more responsive to immunotherapies. In other studies, she and her colleagues have discovered a novel drug, L-NMMA, that targets a molecule known to promote tumor growth and metastasis. They are evaluating the efficacy of combining L-NMMA with another targeted drug, alpelisib (PIQRAY®) to treat TNBC. Preliminary studies indicate that this combination plus chemotherapy is an effective therapeutic approach to treat metaplastic breast cancer, the most aggressive subtype of TNBC.

What’s next: She and her team will continue to study the role of IL12 in response to immunotherapy to identify strategies to improve immunotherapy treatment for patients with TNBC. Also, Dr. Chang will continue to investigate the use of L-NMMA in combination with alpelisib and hopes to develop and conduct preclinical studies that will move to clinical evaluation in the near future.

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Research goal: To develop and test novel potential drug targets for the treatment of triple negative breast cancer (TNBC).

Impact: TNBC is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate is low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for patients with TNBC, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Current investigation: Dr. Chang is utlizing state-of-the-art laboratory models to improve the efficacy of immunotherapy and to test novel combinations of treatments that may be effective against TNBC.

What she’s learned so far: Using these models, her team has identified interleukin 12, a component of the tumor microenvironment, that can be targeted to make tumors more responsive to immunotherapies. She and her colleagues have also discovered a novel signaling inhibitor, L-NMMA,  which targets a specific molecule known to promote tumor growth and metastasis. They are evaluating the efficacy of combining this signaling inhibitor with alpelisib (P13Kα-inhibitor) to treat this aggressive disease.

What’s next: She and her team will continue to test the ability of interleukin 12 to alter the tumor microenvironment to improve immunotherapy treatment for TNBC. They will also continue to test targeting of the signaling inhibitor L-NMMA in combination with alpelisib for treating this aggressive form of breast cancer. Dr. Chang will fully develop these preclinical studies and expects them to move to clinical evaluation in the near future.

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Research goal: To develop and test novel potential drug targets for the treatment of triple negative breast cancer (TNBC).

Impact: TNBC is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate is low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for patients with TNBC, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Current investigation: Dr. Chang is utlizing state-of-the-art laboratory models to improve the efficacy of immunotherapy and to test novel combinations of treatments that may be effective against TNBC.

What she’s learned so far: Using these models, her team has identified interleukin 12, a component of the tumor microenvironment, that can be targeted to make tumors more responsive to immunotherapies. She and her colleagues have also discovered a novel signaling inhibitor, L-NMMA,  which targets a specific molecule known to promote tumor growth and metastasis. They are evaluating the efficacy of combining this signaling inhibitor with alpelisib (P13Kα-inhibitor) to treat this aggressive disease.

What’s next: She and her team will continue to test the ability of interleukin 12 to alter the tumor microenvironment to improve immunotherapy treatment for TNBC. They will also continue to test targeting of the signaling inhibitor L-NMMA in combination with alpelisib for treating this aggressive form of breast cancer. Dr. Chang will fully develop these preclinical studies and expects them to move to clinical evaluation in the near future.

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Director, Methodist Cancer Center
Professor, Weill Cornell Medical College
Professor and Emily Herrmann Chair in Cancer Research, Houston Methodist Hospital

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To identify and test potential drug targets for the treatment of triple-negative breast cancer.

Impact

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate remains low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (TME, the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for TNBC patients, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Progress Thus Far

Dr. Chang and her colleagues discovered that the drug, L-NMMA, targets a molecule known to promote tumor growth and metastasis. Laboratory studies revealed that L-NMMA plus chemotherapy was better at reducing tumor growth and lung metastasis than chemotherapy alone. In the last year, Dr. Chang reported the promising results of a phase 1/2 trial that tested L-NMMA in combination with taxane chemotherapy in patients with advanced or metastatic TNBC. Overall, 45.8 percent of patients that had some response to L-NMMA in combination with a taxane. In patients with locally advanced breast cancer, the response rate was an impressive 81.8 percent with 36.4 percent showing a complete response; and while patients with metastatic TNBC had a 15.4 percent response rate, 53.8 percent received some clinical benefit. Building on her continued interest in the role of immune cells in the TME, Dr. Chang examined the effect of the combination treatment on the levels of immune cells. They found that the levels of neutrophils were increased in patients that responded to the combination, while macrophages (another immune cell type) were increased in non-responders.

What’s next

Further studies are planned to unravel the mechanism behind the neutrophil and macrophage shifts in responders and non-responders, and what these shifts might mean for patient response. Based on the positive results of the phase 1/2 trial, Dr. Chang concluded that L-NMMA and chemotherapy warrants further testing in larger phase 3 trials—if successful, this will move this strategy for treating TNBC and other aggressive breast cancers closer to FDA approval and give hope to these patients with limited treatment options.

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To identify and test potential drug targets for the treatment of triple-negative breast cancer.

Impact

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer and while new immunotherapy drugs have shown some effectiveness in these patients, the response rate remains low. Dr. Chang and her team are testing the hypothesis that modification of the tumor microenvironment (TME, the environment surrounding a tumor) can dramatically improve the response to immune-based novel therapies. Their work may reveal new targeted therapeutic strategies for TNBC patients, who have poor outcomes due to high rates of recurrence, metastatic spread, and lack of approved targeted therapies.

Progress Thus Far

Dr. Chang and her colleagues discovered that the drug, L-NMMA, targets a molecule known to promote tumor growth and metastasis. Laboratory studies revealed that L-NMMA plus chemotherapy was better at reducing tumor growth and lung metastasis than chemotherapy alone. In the last year, Dr. Chang reported the promising results of a phase 1/2 trial that tested L-NMMA in combination with taxane chemotherapy in patients with advanced or metastatic TNBC. Overall, 45.8 percent of patients that had some response to L-NMMA in combination with a taxane. In patients with locally advanced breast cancer, the response rate was an impressive 81.8 percent with 36.4 percent showing a complete response; and while patients with metastatic TNBC had a 15.4 percent response rate, 53.8 percent received some clinical benefit. Building on her continued interest in the role of immune cells in the TME, Dr. Chang examined the effect of the combination treatment on the levels of immune cells. They found that the levels of neutrophils were increased in patients that responded to the combination, while macrophages (another immune cell type) were increased in non-responders.

What’s next

Further studies are planned to unravel the mechanism behind the neutrophil and macrophage shifts in responders and non-responders, and what these shifts might mean for patient response. Based on the positive results of the phase 1/2 trial, Dr. Chang concluded that L-NMMA and chemotherapy warrants further testing in larger phase 3 trials—if successful, this will move this strategy for treating TNBC and other aggressive breast cancers closer to FDA approval and give hope to these patients with limited treatment options.

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Learn more about Michael F. Clarke at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Michael F. Clarke | Researcher | Breast Cancer Research Foundation

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Learn more about Michael F. Clarke at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Karel and Avice Beekhuis Endowed Professor in Cancer Biology
Professor of Internal Medicine
Associate Director, Stem and Regenerative Medicine Institute
Stanford Cancer Institute
Stanford Bio-X

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Michael Clarke, MD is a Professor of Medicine at Stanford University. He is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. His interest is in Stem Cell Biology. In addition to clinical duties in oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and diseases such as cancer and hereditary diseases; and ii) the identification and characterization of cancer stem cells.

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Michael Clarke, MD is a Professor of Medicine at Stanford University. He is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. His interest is in Stem Cell Biology. In addition to clinical duties in oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and diseases such as cancer and hereditary diseases; and ii) the identification and characterization of cancer stem cells. His laboratory is pursuing how perturbations in the self-renewal machinery contribute to human disease. His focus is to aid in the development of more effective treatment therapies for various forms of cancer.

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Michael Clarke, MD is a Professor of Medicine at Stanford University. He is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. His interest is in Stem Cell Biology. In addition to clinical duties in oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and diseases such as cancer and hereditary diseases; and ii) the identification and characterization of cancer stem cells. His laboratory is pursuing how perturbations in the self-renewal machinery contribute to human disease. His focus is to aid in the development of more effective treatment therapies for various forms of cancer.

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Goal: To understand the role of cancer stem cells on tumor cell dormancy, cancer recurrence and metastasis.

Impact: Dr. Clarke’s laboratory was the first to identify breast cancer stem cells as responsible for the growth and spread of breast cancer to distant sites (metastasis). His team is identifying novel therapeutic targets specific for breast cancer stem cells as well as biomarkers that can indicate which patients require adjuvant therapy to prevent breast cancer recurrence. These studies will lead to the development of drugs to target cancer stem cells that are intrinsically resistant to standard therapies and to identify women who are at risk for recurrence and metastasis.

What’s next: Dr. Clarke will follow up on his two novel discoveries: identification of druggable cancer stem cell targets that will be used to develop novel treatments; and characterization of a stem cell specific gene and development of inhibitors of this gene.

Despite advances in the early detection and treatment of breast cancer, many patients will experience a recurrence over their lifetimes, sometimes years after the treatment of their primary cancer. Breast cancer stem cells are thought to be the drivers of recurrence because of their ability to survive cancer therapy and lie dormant for many years. Dr. Clarke is investigating ways to target these cells and is now making small molecule drugs that may eliminate breast cancer stem cells while sparing normal stem cells.

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Goal: To understand the role of cancer stem cells on tumor cell dormancy, cancer recurrence and metastasis.

Impact: Dr. Clarke’s laboratory was the first to identify breast cancer stem cells as responsible for the growth and spread of breast cancer to distant sites (metastasis). His team is identifying novel therapeutic targets specific for breast cancer stem cells as well as biomarkers that can indicate which patients require adjuvant therapy to prevent breast cancer recurrence. These studies will lead to the development of drugs to target cancer stem cells that are intrinsically resistant to standard therapies and to identify women who are at risk for recurrence and metastasis.

What’s next: Dr. Clarke will follow up on his two novel discoveries: identification of druggable cancer stem cell targets that will be used to develop novel treatments; and characterization of a stem cell specific gene and development of inhibitors of this gene.

Despite advances in the early detection and treatment of breast cancer, many patients will experience a recurrence over their lifetimes, sometimes years after the treatment of their primary cancer. Breast cancer stem cells are thought to be the drivers of recurrence because of their ability to survive cancer therapy and lie dormant for many years. Dr. Clarke is investigating ways to target these cells and is now making small molecule drugs that may eliminate breast cancer stem cells while sparing normal stem cells.

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Research area: Effectively targeting breast cancer stem cells, which are thought to be the drivers of recurrence, to develop more effective and less toxic therapeutic options for patients.

Impact: Cancer stem cells are resistant to cancer therapies and can remain dormant for many years after treatment. Dr. Clarke's laboratory was the first to identify breast cancer stem cells, a minority population of cancer cells that are responsible for the growth and spread of breast cancer. Dr. Clarke is now analyzing tumor and clinical data with the aim of discovering ways to target these cells that would reduce the risk of recurrence and the number of breast cancer deaths. Dr. Clarke’s research will lead to more effective and less toxic therapeutic options which will greatly impact the outcomes for patients and ultimately eliminate metastatic breast cancer mortality.

Current research: Dr. Clarke and his team will build on his discoveries which identified the first factors on cancer stem cells that could be preferentially targeted while sparing healthy stem cells. They are also expanding their investigations to develop an inhibitor that will prevent drug-resistant breast tumor cells from surviving and metastasizing.

What he’s learned so far: A major challenge in developing novel treatment to target cancer stem cells is that these cells bear substantial similarities to normal stem cells. Hence, novel treatments must be very specific to the cancer stem cells to avoid serious side effects. Dr. Clarke and his colleagues have developed a method to distinguish cancer stem cells from normal cells. This method has enabled the identification of 20 different stem cell targets that can be used to develop novel drugs for the treatment of triple-negative breast cancer (TNBC) tumors which are highly resistant to current therapies. They have also identified a cancer stem cell gene that appears to regulate tumor stem cell survival and is critical for the establishment, maintenance, and growth of tumors. They have shown that this gene plays a role in the regulation of TNBC stem cells but not normal stem cells. Thus, it provides a potential therapeutic target for TNBC tumors. They have developed an inhibitor of this gene and are continuing efforts to develop other small molecule drugs that specifically target the cancer stem cells while sparing normal stem cells.

What’s next: Dr. Clarke has made two novel discoveries that have the potential to be translated into the clinic: identification of druggable cancer stem cell targets for drug development; and characterization of a stem cell specific gene and development of inhibitors of this gene. Notably, these discoveries constitute the first factors to be identified that enable preferential targeting of cancer stem cells but spare other healthy stem cells. His team will continue to pursue these avenues and ultimately translate their findings to the clinic. They are also continuing their studies of a novel pathway shown to be critical in drug-resistance and metastasis. In the coming year, Dr. Clarke will expand his investigations into mechanisms of this pathway to develop an inhibitor that will prevent drug-resistant breast tumor cells from surviving and metastasizing.

# data[].attributes.field_full_research_summary.processed
Research area: Effectively targeting breast cancer stem cells, which are thought to be the drivers of recurrence, to develop more effective and less toxic therapeutic options for patients.

Impact: Cancer stem cells are resistant to cancer therapies and can remain dormant for many years after treatment. Dr. Clarke's laboratory was the first to identify breast cancer stem cells, a minority population of cancer cells that are responsible for the growth and spread of breast cancer. Dr. Clarke is now analyzing tumor and clinical data with the aim of discovering ways to target these cells that would reduce the risk of recurrence and the number of breast cancer deaths. Dr. Clarke’s research will lead to more effective and less toxic therapeutic options which will greatly impact the outcomes for patients and ultimately eliminate metastatic breast cancer mortality.

Current research: Dr. Clarke and his team will build on his discoveries which identified the first factors on cancer stem cells that could be preferentially targeted while sparing healthy stem cells. They are also expanding their investigations to develop an inhibitor that will prevent drug-resistant breast tumor cells from surviving and metastasizing.

What he’s learned so far: A major challenge in developing novel treatment to target cancer stem cells is that these cells bear substantial similarities to normal stem cells. Hence, novel treatments must be very specific to the cancer stem cells to avoid serious side effects. Dr. Clarke and his colleagues have developed a method to distinguish cancer stem cells from normal cells. This method has enabled the identification of 20 different stem cell targets that can be used to develop novel drugs for the treatment of triple-negative breast cancer (TNBC) tumors which are highly resistant to current therapies. They have also identified a cancer stem cell gene that appears to regulate tumor stem cell survival and is critical for the establishment, maintenance, and growth of tumors. They have shown that this gene plays a role in the regulation of TNBC stem cells but not normal stem cells. Thus, it provides a potential therapeutic target for TNBC tumors. They have developed an inhibitor of this gene and are continuing efforts to develop other small molecule drugs that specifically target the cancer stem cells while sparing normal stem cells.

What’s next: Dr. Clarke has made two novel discoveries that have the potential to be translated into the clinic: identification of druggable cancer stem cell targets for drug development; and characterization of a stem cell specific gene and development of inhibitors of this gene. Notably, these discoveries constitute the first factors to be identified that enable preferential targeting of cancer stem cells but spare other healthy stem cells. His team will continue to pursue these avenues and ultimately translate their findings to the clinic. They are also continuing their studies of a novel pathway shown to be critical in drug-resistance and metastasis. In the coming year, Dr. Clarke will expand his investigations into mechanisms of this pathway to develop an inhibitor that will prevent drug-resistant breast tumor cells from surviving and metastasizing.

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Karel and Avice Beekhuis Endowed Professor in Cancer Biology
Professor of Internal Medicine
Associate Director, Stem and Regenerative Medicine Institute
Stanford Cancer Institute
Stanford Bio-X

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Identifying effective methods for targeting cancer stem cells which play a significant role in breast cancer recurrence and metastasis.

Impact

Despite advances in the early detection and treatment of breast cancer, many patients will experience a recurrence, sometimes years after the treatment of their primary cancer. Dr. Clarke's laboratory was the first to identify breast cancer stem cells (CSCs) as major contributors to metastasis—the spread of breast cancer to distant sites. CSCs are also potential drivers of recurrence because of their ability to survive cancer therapy and lie dormant for many years. CSCs are a minor population within tumors but eliminating them may be required to prevent cancer from returning. Dr. Clarke and his team’s work focuses on identifying new therapeutic targets that will specifically eliminate breast CSCs, as well as biomarkers to signal which patients will require adjuvant therapy to prevent breast cancer recurrence.

Progress Thus Far

A major challenge in developing therapies targeting CSCs is that they are very similar to normal stem cells. Hence, new treatments must be specific to the CSCs to avoid serious side effects. Dr. Clarke’s team developed a method to distinguish CSCs from normal cells, and subsequently identified 40 different stem cell targets that could be used to design therapies for triple-negative breast cancer (TNBC) tumors, which are highly resistant to current therapies. They also identified a CSC-specific gene that appears to regulate tumor stem cell survival and is critical for the establishment, maintenance, and growth of tumors. The team is working on a drug to block this gene and they found a few promising candidates, including a drug that effectively hits its target while not affecting normal cells.

What’s next

In the next year, Dr. Clarke’s team will further refine the drug they developed to eradicate CSCs. This will lay the groundwork for further confirmatory studies in the lab before the drug can progress to a clinical trial.

# data[].attributes.field_research.processed
Identifying effective methods for targeting cancer stem cells which play a significant role in breast cancer recurrence and metastasis.

Impact

Despite advances in the early detection and treatment of breast cancer, many patients will experience a recurrence, sometimes years after the treatment of their primary cancer. Dr. Clarke's laboratory was the first to identify breast cancer stem cells (CSCs) as major contributors to metastasis—the spread of breast cancer to distant sites. CSCs are also potential drivers of recurrence because of their ability to survive cancer therapy and lie dormant for many years. CSCs are a minor population within tumors but eliminating them may be required to prevent cancer from returning. Dr. Clarke and his team’s work focuses on identifying new therapeutic targets that will specifically eliminate breast CSCs, as well as biomarkers to signal which patients will require adjuvant therapy to prevent breast cancer recurrence.

Progress Thus Far

A major challenge in developing therapies targeting CSCs is that they are very similar to normal stem cells. Hence, new treatments must be specific to the CSCs to avoid serious side effects. Dr. Clarke’s team developed a method to distinguish CSCs from normal cells, and subsequently identified 40 different stem cell targets that could be used to design therapies for triple-negative breast cancer (TNBC) tumors, which are highly resistant to current therapies. They also identified a CSC-specific gene that appears to regulate tumor stem cell survival and is critical for the establishment, maintenance, and growth of tumors. The team is working on a drug to block this gene and they found a few promising candidates, including a drug that effectively hits its target while not affecting normal cells.

What’s next

In the next year, Dr. Clarke’s team will further refine the drug they developed to eradicate CSCs. This will lay the groundwork for further confirmatory studies in the lab before the drug can progress to a clinical trial.

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Learn more about Graham A. Colditz at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Graham A. Colditz | Researcher | Breast Cancer Research Foundation

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Learn more about Graham A. Colditz at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Niess-Gain Professor of Surgery and Professor of Medicine
Chief, Division of Public Health Sciences, Department of Surgery
Associate Director Prevention and Control
Alvin J. Siteman Cancer Center
Deputy Director, Institute for Public Health

# data[].attributes.metatag_normalized[].attributes.content.name
Washington University School of Medicine

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Graham A. Colditz, DrPH, MD, MPH is an epidemiologist and public health expert with a longstanding interest in the causes and prevention of chronic disease, particularly among women. With a commitment to identifying strategies for prevention of breast cancer, Dr. Colditz studies benign breast disease and other markers for risk of breast cancer. Dr. Colditz described the increase in risk of breast cancer with use of combined estrogen plus progestin therapy and a significant increase in risk with increasing duration of use.

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Graham A. Colditz, DrPH, MD, MPH is an epidemiologist and public health expert with a longstanding interest in the causes and prevention of chronic disease, particularly among women. With a commitment to identifying strategies for prevention of breast cancer, Dr. Colditz studies benign breast disease and other markers for risk of breast cancer. Dr. Colditz described the increase in risk of breast cancer with use of combined estrogen plus progestin therapy and a significant increase in risk with increasing duration of use. Mortality from breast cancer was also elevated among current users (NEJM 1995). These data were confirmed by the WHI. He documented in prospective data the importance of proliferative benign lesions and risk of subsequent breast cancer (JAMA 1992; NEJM 1999) and the potential for childhood and adolescent diet, alcohol, and adiposity to modify risk of premalignant and invasive breast cancers. His research continues to focus on this time period in women’s lives and prevention of breast cancer. He is among the most highly cited medical researchers in the world.

Dr. Colditz developed the award-winning Your Disease Risk website (www.yourdiseaserisk.wustl.edu) which communicates tailored prevention messages to the public. He has published over 1100 peer-reviewed publications, six books and contributed to reports for the National Academy of Medicine and National Academies of Science.

Dr. Colditz has served in numerous leadership roles. He was the editor-in-chief of the journal Cancer Causes and Control and has contributed to reports of the Surgeon General on Tobacco and Health. In October 2006, on the basis of professional achievement and commitment to public health, Dr. Colditz was elected to membership of the Institute of Medicine (now National Academy of Medicine), an independent body that advises the U.S. government on issues affecting public health. He received the ACS Medal of Honor in 2011, the AACR-AACS award in 2012, and the ACSO-ACS award in 2014, all recognizing his research in cancer prevention and control.

# data[].attributes.body.processed
Graham A. Colditz, DrPH, MD, MPH is an epidemiologist and public health expert with a longstanding interest in the causes and prevention of chronic disease, particularly among women. With a commitment to identifying strategies for prevention of breast cancer, Dr. Colditz studies benign breast disease and other markers for risk of breast cancer. Dr. Colditz described the increase in risk of breast cancer with use of combined estrogen plus progestin therapy and a significant increase in risk with increasing duration of use. Mortality from breast cancer was also elevated among current users (NEJM 1995). These data were confirmed by the WHI. He documented in prospective data the importance of proliferative benign lesions and risk of subsequent breast cancer (JAMA 1992; NEJM 1999) and the potential for childhood and adolescent diet, alcohol, and adiposity to modify risk of premalignant and invasive breast cancers. His research continues to focus on this time period in women’s lives and prevention of breast cancer. He is among the most highly cited medical researchers in the world.

Dr. Colditz developed the award-winning Your Disease Risk website (www.yourdiseaserisk.wustl.edu) which communicates tailored prevention messages to the public. He has published over 1100 peer-reviewed publications, six books and contributed to reports for the National Academy of Medicine and National Academies of Science.

Dr. Colditz has served in numerous leadership roles. He was the editor-in-chief of the journal Cancer Causes and Control and has contributed to reports of the Surgeon General on Tobacco and Health. In October 2006, on the basis of professional achievement and commitment to public health, Dr. Colditz was elected to membership of the Institute of Medicine (now National Academy of Medicine), an independent body that advises the U.S. government on issues affecting public health. He received the ACS Medal of Honor in 2011, the AACR-AACS award in 2012, and the ACSO-ACS award in 2014, all recognizing his research in cancer prevention and control.

# data[].attributes.field_current_research.value
Research Area: To understand how early life behaviors influence future breast cancer risk and to refine risk assessment methods.

Impact: It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz is focused on how those choices (including diet, alcohol use, exercise, and sleep), when made during childhood and adolescence, impact a person's future risk of breast cancer. His studies may lead to the development of targeted interventions and strategies to promote a healthy lifestyle in young adults to reduce the risk of breast cancer.

Progress Thus Far: Previously, Dr. Colditz found that dietary choices (nuts and fiber) during adolescence may counter the effect of alcohol consumption on breast cancer risk. Girls who drank alcohol and consumed nuts or had a higher than normal intake of dietary fiber had a significantly lower risk of breast cancer than those who did not consume nuts or who had a diet with lower fiber. In the last year, his team reported the combined effects of adolescent dietary intake along with alcohol intake on risk of benign breast disease, a risk factor for future breast cancer in young women. They found that higher nut intake in adolescence (including peanut butter) was associated with lower subsequent risk of benign breast disease and this protection persisted among women who drank alcohol. Adolescents who drank alcohol in high school or had a low intake of fiber almost doubled their risk of benign breast disease. This risk, however, could be attenuated by consuming nuts.

What's next: The team will continue to study how modifiable factors such as diet affect or reduce the risk of breast cancer. In addition, they will examine how these factors affect the rate of transition between breast cancer states such as the progression from benign breast disease to breast cancer.

# data[].attributes.field_current_research.processed
Research Area: To understand how early life behaviors influence future breast cancer risk and to refine risk assessment methods.

Impact: It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz is focused on how those choices (including diet, alcohol use, exercise, and sleep), when made during childhood and adolescence, impact a person's future risk of breast cancer. His studies may lead to the development of targeted interventions and strategies to promote a healthy lifestyle in young adults to reduce the risk of breast cancer.

Progress Thus Far: Previously, Dr. Colditz found that dietary choices (nuts and fiber) during adolescence may counter the effect of alcohol consumption on breast cancer risk. Girls who drank alcohol and consumed nuts or had a higher than normal intake of dietary fiber had a significantly lower risk of breast cancer than those who did not consume nuts or who had a diet with lower fiber. In the last year, his team reported the combined effects of adolescent dietary intake along with alcohol intake on risk of benign breast disease, a risk factor for future breast cancer in young women. They found that higher nut intake in adolescence (including peanut butter) was associated with lower subsequent risk of benign breast disease and this protection persisted among women who drank alcohol. Adolescents who drank alcohol in high school or had a low intake of fiber almost doubled their risk of benign breast disease. This risk, however, could be attenuated by consuming nuts.

What's next: The team will continue to study how modifiable factors such as diet affect or reduce the risk of breast cancer. In addition, they will examine how these factors affect the rate of transition between breast cancer states such as the progression from benign breast disease to breast cancer.

# data[].attributes.field_full_research_summary.value
Research area: Identifying potential prevention strategies to reduce breast cancer risk starting early in life.

Impact: It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz is focused on how those choices, when made during childhood and adolescence, impact a person’s future risk of breast cancer. His studies may lead to the development of targeted interventions and strategies to promote a healthy lifestyle in young adults to reduce the risk of breast cancer.

Current investigation: He and his team are evaluating the relationship of childhood and adolescent lifestyle factors on breast cancer risk specifically focusing on how growth velocity and mammographic density affect lifetime risk of breast cancer.

What he’s learned so far: Previously, Dr. Colditz has shown that dietary choices (nuts and fiber) may counter the effect of alcohol consumption on breast cancer risk: girls who drank alcohol and consumed nuts or had a higher than normal intake of dietary fiber had a significantly lower risk of breast cancer than those who did not consume nuts or who had a diet with lower fiber.

What’s next: The team will continue to study how diet can modify or reduce the risk of breast cancer. In addition, they will continue their studies examining the association of dietary patterns in adolescence with the risk of premalignant (benign) breast lesions, as well as how the timing of physical activity in childhood and adolescence impacts the future risk of breast cancer.

# data[].attributes.field_full_research_summary.processed
Research area: Identifying potential prevention strategies to reduce breast cancer risk starting early in life.

Impact: It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz is focused on how those choices, when made during childhood and adolescence, impact a person’s future risk of breast cancer. His studies may lead to the development of targeted interventions and strategies to promote a healthy lifestyle in young adults to reduce the risk of breast cancer.

Current investigation: He and his team are evaluating the relationship of childhood and adolescent lifestyle factors on breast cancer risk specifically focusing on how growth velocity and mammographic density affect lifetime risk of breast cancer.

What he’s learned so far: Previously, Dr. Colditz has shown that dietary choices (nuts and fiber) may counter the effect of alcohol consumption on breast cancer risk: girls who drank alcohol and consumed nuts or had a higher than normal intake of dietary fiber had a significantly lower risk of breast cancer than those who did not consume nuts or who had a diet with lower fiber.

What’s next: The team will continue to study how diet can modify or reduce the risk of breast cancer. In addition, they will continue their studies examining the association of dietary patterns in adolescence with the risk of premalignant (benign) breast lesions, as well as how the timing of physical activity in childhood and adolescence impacts the future risk of breast cancer.

# data[].attributes.field_job_title
Niess-Gain Professor of Surgery and Professor of Medicine
Chief, Division of Public Health Sciences, Department of Surgery
Associate Director Prevention and Control
Alvin J. Siteman Cancer Center
Deputy Director, Institute for Public Health

# data[].attributes.field_research.value
To understand how early life behaviors influence future breast cancer risk and to refine risk assessment methods.

Impact

It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz’s research has focused on how those choices (including diet, alcohol use, exercise, and sleep), when made during childhood and adolescence, impact a person's future risk of breast cancer. His findings showed that higher nut intake in adolescence (including peanut butter) was associated with lower subsequent risk of benign breast disease and this protection persisted among women who drank alcohol. Adolescents who drank alcohol in high school or had a low intake of fiber almost doubled their risk of benign breast disease. This risk, however, could be attenuated by consuming nuts. His studies may lead to strategies that promote a healthy lifestyle in young adults to reduce the risk of breast cancer. In his continued efforts to study the relationship between benign breast disease and risk of breast cancer, Dr. Colditz and his colleagues are analyzing mammograms accumulated from routine screening of large cohorts of patients over time and hope to develop refined models to predict when benign breast disease evolves to become breast cancer—these studies will improve risk management and inform personalized prevention strategies.

Progress Thus Far

Dr. Colditz continues to examine how modifiable factors such as diet affect the rate of transition between breast cancer states such as the progression from benign breast disease to breast cancer. In the past year, his team has been evaluating how mammographic data can be used to monitor this progression. They have assembled over 9,000 mammograms obtained from screening of 954 women for over ten years, analyzed the images, and applied several sophisticated modeling techniques. They have demonstrated, for the first time, that analysis of repeated mammograms over 10 years can detect a divergence in breast density more than 6 months prior to a breast cancer diagnosis.

What's next

Building on their findings, the team will expand their analysis and include a questionnaire and genetic marker assessment to further refine their risk prediction model, while also working to enhance the models to predict risk of ductal carcinoma in situ (DCIS) and triple-negative breast cancer. These studies may provide insight into the dynamic transition that occurs as normal breast tissue evolves to become breast cancer. Moreover, Dr. Colditz results will demonstrate that mammograms that are routinely available can be used to understand an individual’s personalized risk over time.

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To understand how early life behaviors influence future breast cancer risk and to refine risk assessment methods.

Impact

It is estimated that nearly a third of breast cancers could be prevented by lifestyle choices, particularly those that support and maintain a healthy weight, including diet and exercise. Dr. Colditz’s research has focused on how those choices (including diet, alcohol use, exercise, and sleep), when made during childhood and adolescence, impact a person's future risk of breast cancer. His findings showed that higher nut intake in adolescence (including peanut butter) was associated with lower subsequent risk of benign breast disease and this protection persisted among women who drank alcohol. Adolescents who drank alcohol in high school or had a low intake of fiber almost doubled their risk of benign breast disease. This risk, however, could be attenuated by consuming nuts. His studies may lead to strategies that promote a healthy lifestyle in young adults to reduce the risk of breast cancer. In his continued efforts to study the relationship between benign breast disease and risk of breast cancer, Dr. Colditz and his colleagues are analyzing mammograms accumulated from routine screening of large cohorts of patients over time and hope to develop refined models to predict when benign breast disease evolves to become breast cancer—these studies will improve risk management and inform personalized prevention strategies.

Progress Thus Far

Dr. Colditz continues to examine how modifiable factors such as diet affect the rate of transition between breast cancer states such as the progression from benign breast disease to breast cancer. In the past year, his team has been evaluating how mammographic data can be used to monitor this progression. They have assembled over 9,000 mammograms obtained from screening of 954 women for over ten years, analyzed the images, and applied several sophisticated modeling techniques. They have demonstrated, for the first time, that analysis of repeated mammograms over 10 years can detect a divergence in breast density more than 6 months prior to a breast cancer diagnosis.

What's next

Building on their findings, the team will expand their analysis and include a questionnaire and genetic marker assessment to further refine their risk prediction model, while also working to enhance the models to predict risk of ductal carcinoma in situ (DCIS) and triple-negative breast cancer. These studies may provide insight into the dynamic transition that occurs as normal breast tissue evolves to become breast cancer. Moreover, Dr. Colditz results will demonstrate that mammograms that are routinely available can be used to understand an individual’s personalized risk over time.

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Learn more about Steven W. Cole at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Steven W. Cole | Researcher | Breast Cancer Research Foundation

# data[].attributes.metatag_normalized[].attributes.content
Learn more about Steven W. Cole at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Division of Hematology-Oncology
Department of Psychiatry & Biobehavioral Sciences
David Geffen School of Medicine

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Steven W. Cole, PhD is a Professor of Medicine in the Division of Hematology-Oncology at the UCLA School of Medicine. His research maps the molecular pathways by which social and environmental factors influence the activity of human, viral, and tumor genomes.

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Steven W. Cole, PhD is a Professor of Medicine in the Division of Hematology-Oncology at the UCLA School of Medicine. His research maps the molecular pathways by which social and environmental factors influence the activity of human, viral, and tumor genomes.  He pioneered the use of functional genomics approaches in social and behavioral research and has mapped the signal transduction pathways by which social factors enhance replication of viruses (e.g., HIV-1 and HHV-8), alter expression of immune response genes (e.g., IL-6 and Interferon-beta), and up-regulate expression of pro-metastatic genes by human breast and ovarian cancer cells.  His research uses computational modeling strategies to identify transcription factors that mediate socio-environmental influences on gene expression and genetic polymorphisms that modify those effects to create Gene x Environment interactions.  Dr. Cole is member of the Jonsson Comprehensive Cancer Center, the Norman Cousins Center, the UCLA Molecular Biology Institute, and the NCI Network on Biobehavioral Pathways in Cancer, and he holds a joint appointment in UCLA’s Department of Psychiatry and Biobehavioral Sciences.

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Steven W. Cole, PhD is a Professor of Medicine in the Division of Hematology-Oncology at the UCLA School of Medicine. His research maps the molecular pathways by which social and environmental factors influence the activity of human, viral, and tumor genomes. He pioneered the use of functional genomics approaches in social and behavioral research and has mapped the signal transduction pathways by which social factors enhance replication of viruses (e.g., HIV-1 and HHV-8), alter expression of immune response genes (e.g., IL-6 and Interferon-beta), and up-regulate expression of pro-metastatic genes by human breast and ovarian cancer cells. His research uses computational modeling strategies to identify transcription factors that mediate socio-environmental influences on gene expression and genetic polymorphisms that modify those effects to create Gene x Environment interactions. Dr. Cole is member of the Jonsson Comprehensive Cancer Center, the Norman Cousins Center, the UCLA Molecular Biology Institute, and the NCI Network on Biobehavioral Pathways in Cancer, and he holds a joint appointment in UCLA’s Department of Psychiatry and Biobehavioral Sciences.

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Research Area: Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far: Drs. Cole and Bower are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now also expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_current_research.processed
Research Area: Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far: Drs. Cole and Bower are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next: The team will continue to analyze the results of their preclinical studies and define the biological pathways through which psychological and social processes impact breast tumor biology. They will now also expand the novel digital approaches for delivering these interventions to larger and more diverse groups of women. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_full_research_summary.value
Research area: Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation— this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body.  They hope to identify novel targets and interventions that improve quality and potentially length of life for patients with breast cancer.

Current investigation: Drs. Cole and Bower are examining the links between psychological stress and immunity in breast cancer with a focus on inflammation.

What they’ve learned so far: Drs. Cole and Bower have developed an experimental model of breast cancer metastasis to study specific neural and immune processes through which stress may influence breast tumor growth and spread. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain’s reward system. In addition, they have developed and optimized an intervention protocol to reduce stress in breast cancer patients.

What’s next: The team has developed a preclinical model to test whether activation of reward-related regions in the brain has a beneficial effect on breast tumor development. They will continue to investigate the link between stress and breast cancer and to identify targets for intervention. In addition, they will develop an online version of their mindfulness-based intervention for breast cancer survivors which has been shown to reduce stress, enhance well-being, and lower inflammation. Both lines of research are designed to establish new paradigms for blocking the stress effect in the context of human breast cancer.

# data[].attributes.field_full_research_summary.processed
Research area: Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact: Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation— this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body.  They hope to identify novel targets and interventions that improve quality and potentially length of life for patients with breast cancer.

Current investigation: Drs. Cole and Bower are examining the links between psychological stress and immunity in breast cancer with a focus on inflammation.

What they’ve learned so far: Drs. Cole and Bower have developed an experimental model of breast cancer metastasis to study specific neural and immune processes through which stress may influence breast tumor growth and spread. They have shown that stress-induced changes in tumor biology can be blocked by stimulating the brain’s reward system. In addition, they have developed and optimized an intervention protocol to reduce stress in breast cancer patients.

What’s next: The team has developed a preclinical model to test whether activation of reward-related regions in the brain has a beneficial effect on breast tumor development. They will continue to investigate the link between stress and breast cancer and to identify targets for intervention. In addition, they will develop an online version of their mindfulness-based intervention for breast cancer survivors which has been shown to reduce stress, enhance well-being, and lower inflammation. Both lines of research are designed to establish new paradigms for blocking the stress effect in the context of human breast cancer.

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Professor, Division of Hematology-Oncology
Department of Psychiatry & Biobehavioral Sciences
David Geffen School of Medicine

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Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact

Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far

Drs. Cole and Bower are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. Building on their recent findings that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system, they have established a laboratory model system to test how stimulation impacts breast cancer growth and metastasis. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next

The team will continue to optimize the models they developed and determine whether manipulation of the reward system can impact the propensity towards metastasis and how neural and cellular mechanisms are involved. These studies will ultimately help to refine clinical interventions that have the potential to enhance reward-promoting effects in breast cancer patients. They will also expand the use of novel digital approaches for delivering behavioral interventions to more effectively reach a broad and diverse range of women with breast cancer. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

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Studying the biological pathways that link psychological stress and breast cancer outcomes, with a focus on the nervous and immune systems.

Impact

Patients who have been diagnosed and treated for breast cancer experience many forms of stress including psychological stress which can activate the immune response and cause inflammation—this negatively impacts breast cancer outcomes. Compelling evidence has emerged that indicates that the immune response and inflammation play a role in tumor initiation, progression, and metastatic spread. Drs. Cole and Bower are focusing on the role of the nervous and immune systems in translating stress from brain to body. These studies aim to define new “positive neurobiology” pathways that can be translated into clinical interventions. Through this work, they hope to establish new paradigms for blocking stress in order to promote both the quality and potentially the length of breast cancer survivorship.

Progress Thus Far

Drs. Cole and Bower are conducting several interrelated lines of research into the association between psychosocial stressors and tumor characteristics in women with early-stage breast cancer. This includes examination of neural processes that link chronic stress and inflammatory processes relevant for tumor progression, as well as intervention studies to reduce stress and identify neuroendocrine pathways that impact tumor biology. Building on their recent findings that stress-induced changes in tumor biology can be blocked by stimulating the brain's reward system, they have established a laboratory model system to test how stimulation impacts breast cancer growth and metastasis. In addition, they have developed and optimized an online version of their mindfulness-based intervention for breast cancer survivors. They have demonstrated that this intervention is effective in reducing depression, enhancing well-being, and improving tumor-relevant immune processes in younger breast cancer survivors.

What’s next

The team will continue to optimize the models they developed and determine whether manipulation of the reward system can impact the propensity towards metastasis and how neural and cellular mechanisms are involved. These studies will ultimately help to refine clinical interventions that have the potential to enhance reward-promoting effects in breast cancer patients. They will also expand the use of novel digital approaches for delivering behavioral interventions to more effectively reach a broad and diverse range of women with breast cancer. These lines of research are designed to establish new parameters for blocking the stress effect in the context of human breast cancer.

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Learn more about David Cortez at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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David Cortez | Researcher | Breast Cancer Research Foundation

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Learn more about David Cortez at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Chair and Professor, Department of Biochemistry
Richard Armstrong Professor for Innovation in Biochemistry
Associate Director of Basic Sciences,
Vanderbilt-Ingram Cancer Center

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Vanderbilt University School of Medicine

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Dr. Cortez graduated summa cum laude from the University of Illinois at Champaign-Urbana with Highest Honors in Biology and Biochemistry. He received his doctorate in 1997 in Molecular Cancer Biology from Duke University. After postdoctoral training as a Jane Coffin Childs Fellow at the Baylor College of Medicine, Dr. Cortez joined the Vanderbilt faculty in 2002. He was promoted to Associate Professor in 2007 and Professor of Biochemistry and Ingram Professor of Cancer Research in 2009. Dr.

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Dr. Cortez graduated summa cum laude from the University of Illinois at Champaign-Urbana with Highest Honors in Biology and Biochemistry. He received his doctorate in 1997 in Molecular Cancer Biology from Duke University. After postdoctoral training as a Jane Coffin Childs Fellow at the Baylor College of Medicine, Dr. Cortez joined the Vanderbilt faculty in 2002. He was promoted to Associate Professor in 2007 and Professor of Biochemistry and Ingram Professor of Cancer Research in 2009. Dr. Cortez is Director of Graduate Studies in the Department of Biochemistry, and a member of the Editorial Boards of the journals Cell Reports, Molecular and Cellular Biology, and Journal of Biochemistry. He became co-leader of the Genome Maintenance Program in the Vanderbilt-Ingram Cancer Center upon its inception in 2007.

Dr. Cortez’s research focuses on the mechanisms that maintain genome integrity. His research has been published in journals including Science, Genes and Development, Cell Reports, Molecular and Cellular Biology, Journal of Biological Chemistry, Proceedings of the National Academy of Sciences, Cancer Research, and Molecular Cell. He has received several awards recognizing his scientific achievements including the Howard Temin Award from the National Cancer Institute, the Wilson S. Stone Memorial Award, and a Pew Scholar Award from the Pew Charitable Trusts.

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Dr. Cortez graduated summa cum laude from the University of Illinois at Champaign-Urbana with Highest Honors in Biology and Biochemistry. He received his doctorate in 1997 in Molecular Cancer Biology from Duke University. After postdoctoral training as a Jane Coffin Childs Fellow at the Baylor College of Medicine, Dr. Cortez joined the Vanderbilt faculty in 2002. He was promoted to Associate Professor in 2007 and Professor of Biochemistry and Ingram Professor of Cancer Research in 2009. Dr. Cortez is Director of Graduate Studies in the Department of Biochemistry, and a member of the Editorial Boards of the journals Cell Reports, Molecular and Cellular Biology, and Journal of Biochemistry. He became co-leader of the Genome Maintenance Program in the Vanderbilt-Ingram Cancer Center upon its inception in 2007.

Dr. Cortez’s research focuses on the mechanisms that maintain genome integrity. His research has been published in journals including Science, Genes and Development, Cell Reports, Molecular and Cellular Biology, Journal of Biological Chemistry, Proceedings of the National Academy of Sciences, Cancer Research, and Molecular Cell. He has received several awards recognizing his scientific achievements including the Howard Temin Award from the National Cancer Institute, the Wilson S. Stone Memorial Award, and a Pew Scholar Award from the Pew Charitable Trusts.

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Goal: To identify new strategies that would improve outcomes for patients with triple-negative breast cancer (TNBC).

Impact: Dr. Cortez is developing strategies to overcome resistance to a targeted therapy (olaparib) for BRCA-mutation associated cancers. These cancers have a higher likelihood of also being triple-negative (TNBC). His findings could expand the number of patients who may benefit from olaparib and improve outcomes for more patients with TNBC.

What’s next: He and his team will continue to investigate resistance mechanisms and, more generally, to understand how tumor cell defects in DNA repair provide opportunities for other therapies like olaparib.

In 2017, the first targeted therapy for BRCA mutation-associated cancers, olaparib (Lymparza®), was approved by the FDA.  This was followed by approval of a second targeted therapy in the same class called talazoparib (Talzenna®). These drugs are in a class of drugs called PARP-inhibitors which work by targeting a protein called PARP. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death. Unfortunately, as with most therapies, resistance to PARP inhibitors can arise. Dr. Cortez is developing strategies to overcome resistance to olaparib and other drugs like it so that more patients can benefit from this therapy.

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Goal: To identify new strategies that would improve outcomes for patients with triple-negative breast cancer (TNBC).

Impact: Dr. Cortez is developing strategies to overcome resistance to a targeted therapy (olaparib) for BRCA-mutation associated cancers. These cancers have a higher likelihood of also being triple-negative (TNBC). His findings could expand the number of patients who may benefit from olaparib and improve outcomes for more patients with TNBC.

What’s next: He and his team will continue to investigate resistance mechanisms and, more generally, to understand how tumor cell defects in DNA repair provide opportunities for other therapies like olaparib.

In 2017, the first targeted therapy for BRCA mutation-associated cancers, olaparib (Lymparza®), was approved by the FDA.  This was followed by approval of a second targeted therapy in the same class called talazoparib (Talzenna®). These drugs are in a class of drugs called PARP-inhibitors which work by targeting a protein called PARP. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death. Unfortunately, as with most therapies, resistance to PARP inhibitors can arise. Dr. Cortez is developing strategies to overcome resistance to olaparib and other drugs like it so that more patients can benefit from this therapy.

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Research area: Understanding the defects in DNA damage response that cause cancer and to develop methods to target this response and develop more effective treatments for patients with triple-negative breast cancer (TNBC).

Impact: Defects in the BRCA1, BRCA2, and other DNA repair genes cause inherited breast cancer. BRCA-associated cancers have a higher likelihood of also being triple-negative (TNBC), a subset of breast cancer with fewer treatment options and higher mortality. The first targeted therapy for BRCA-driven breast cancers, olaparib, was approved in 2017. Olaparib targets an enzyme called PARP which is used by cells to repair DNA damage. Unfortunately, as with most therapies, resistance can arise. Dr. Cortez is seeking to understand resistance mechanisms and specifically to understand how the DNA repair process provides opportunities for improved therapies like olaparib. They hope to identify new drug targets and to develop new strategies that will allow more patients to benefit from olaparib and other drugs like it.

Current investigation: Dr. Cortez is defining the DNA repair mechanisms that impact the efficacy of anti-DNA damage response treatments such as olaparib. In addition, he and his team will identify drug targets that may provide new opportunities for targeted therapies.

What he’s learned so far: Precise replication of DNA requires specific dynamics at the replication fork, a fork-like structure that both stabilizes the DNA and aligns the separated strands with the replication machinery. Dr. Cortez and his colleagues have identified RADX as a protein involved replication fork dynamics, making it an important factor in DNA damage repair and sensitivity to PARP-inhibitors and DNA-damaging cancer treatments. While inactivation of RADX and other fork protection proteins causes genome instability and tumorigenesis, it also provides opportunities for combination anti-DNA damage response therapies.

What’s next: He and his team will continue their studies to understand the mechanisms of DNA repair, which is essential for understanding the vulnerabilities of cells that are deficient in this process. Specifically, they will continue to investigate the proteins and pathways involved as potential biomarkers and new therapeutic targets. They plan to translate their findings into clinically useful information in collaboration with clinicians conducting ongoing clinical trials.

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Research area: Understanding the defects in DNA damage response that cause cancer and to develop methods to target this response and develop more effective treatments for patients with triple-negative breast cancer (TNBC).

Impact: Defects in the BRCA1, BRCA2, and other DNA repair genes cause inherited breast cancer. BRCA-associated cancers have a higher likelihood of also being triple-negative (TNBC), a subset of breast cancer with fewer treatment options and higher mortality. The first targeted therapy for BRCA-driven breast cancers, olaparib, was approved in 2017. Olaparib targets an enzyme called PARP which is used by cells to repair DNA damage. Unfortunately, as with most therapies, resistance can arise. Dr. Cortez is seeking to understand resistance mechanisms and specifically to understand how the DNA repair process provides opportunities for improved therapies like olaparib. They hope to identify new drug targets and to develop new strategies that will allow more patients to benefit from olaparib and other drugs like it.

Current investigation: Dr. Cortez is defining the DNA repair mechanisms that impact the efficacy of anti-DNA damage response treatments such as olaparib. In addition, he and his team will identify drug targets that may provide new opportunities for targeted therapies.

What he’s learned so far: Precise replication of DNA requires specific dynamics at the replication fork, a fork-like structure that both stabilizes the DNA and aligns the separated strands with the replication machinery. Dr. Cortez and his colleagues have identified RADX as a protein involved replication fork dynamics, making it an important factor in DNA damage repair and sensitivity to PARP-inhibitors and DNA-damaging cancer treatments. While inactivation of RADX and other fork protection proteins causes genome instability and tumorigenesis, it also provides opportunities for combination anti-DNA damage response therapies.

What’s next: He and his team will continue their studies to understand the mechanisms of DNA repair, which is essential for understanding the vulnerabilities of cells that are deficient in this process. Specifically, they will continue to investigate the proteins and pathways involved as potential biomarkers and new therapeutic targets. They plan to translate their findings into clinically useful information in collaboration with clinicians conducting ongoing clinical trials.

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Chair and Professor, Department of Biochemistry
Richard Armstrong Professor for Innovation in Biochemistry
Associate Director of Basic Sciences,
Vanderbilt-Ingram Cancer Center

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For basic scientists like myself, BCRF funding encourages us to think about how our research can be directed to relieve the suffering and death caused by breast cancer. I know that this mission has influenced and continues to impact my research priorities. – Dr. Cortez

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For basic scientists like myself, BCRF funding encourages us to think about how our research can be directed to relieve the suffering and death caused by breast cancer. I know that this mission has influenced and continues to impact my research priorities. – Dr. Cortez

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Understanding the defects in DNA damage response that cause cancer for the development of more effective treatments for triple-negative breast cancer.

Impact

Targeting DNA, DNA repair, and DNA replication is a widely used strategy for cancer therapies including radiation and most chemotherapies. These therapies work by increasing DNA damage, which is particularly lethal to cancer cells. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on a protein called PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death and inhibitors of PARP (e.g., oloparib/Lynparza® and talazoparib/Talzenna®) have been approved to treat cancers with defects in genes required for DNA repair such as BRCA1 and BRCA2. Unfortunately, PARP inhibitors do not work for all patients and drug resistance is a problem. Dr. Cortez is seeking to understand resistance mechanisms—specifically how the DNA repair process provides opportunities for improved therapies like olaparib—in order to identify new drug targets and strategies that will allow more patients to benefit from olaparib and other drugs like it.

Progress Thus Far

Precise replication of DNA requires specific dynamics at the replication fork, a fork-like structure that both stabilizes the DNA and aligns the separated strands with the replication machinery. Dr. Cortez and his colleagues have identified RADX as a protein involved in replication fork dynamics, making it an important factor in DNA damage repair and consequently DNA-damaging cancer treatments. While inactivation of RADX and other replication fork proteins causes genome instability and tumorigenesis, it also makes the tumor cells vulnerable to combination anti-DNA damage response therapies. Dr. Cortez and his team discovered two pathways that regulate how cells respond to chemotherapeutic agents that damage DNA and interfere with the process of DNA repair.

What's next

Building on his findings, Dr. Cortez will continue to study these replication stress response pathways with an emphasis on defining how they determine the fate of cancer cells treated with PARP inhibitors, chemotherapeutic, and other agents. In ongoing work with his clinical colleagues, his team will also investigate drug combinations that can work to overcome PARP inhibitor resistance mechanisms.

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Understanding the defects in DNA damage response that cause cancer for the development of more effective treatments for triple-negative breast cancer.

Impact

Targeting DNA, DNA repair, and DNA replication is a widely used strategy for cancer therapies including radiation and most chemotherapies. These therapies work by increasing DNA damage, which is particularly lethal to cancer cells. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on a protein called PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death and inhibitors of PARP (e.g., oloparib/Lynparza® and talazoparib/Talzenna®) have been approved to treat cancers with defects in genes required for DNA repair such as BRCA1 and BRCA2. Unfortunately, PARP inhibitors do not work for all patients and drug resistance is a problem. Dr. Cortez is seeking to understand resistance mechanisms—specifically how the DNA repair process provides opportunities for improved therapies like olaparib—in order to identify new drug targets and strategies that will allow more patients to benefit from olaparib and other drugs like it.

Progress Thus Far

Precise replication of DNA requires specific dynamics at the replication fork, a fork-like structure that both stabilizes the DNA and aligns the separated strands with the replication machinery. Dr. Cortez and his colleagues have identified RADX as a protein involved in replication fork dynamics, making it an important factor in DNA damage repair and consequently DNA-damaging cancer treatments. While inactivation of RADX and other replication fork proteins causes genome instability and tumorigenesis, it also makes the tumor cells vulnerable to combination anti-DNA damage response therapies. Dr. Cortez and his team discovered two pathways that regulate how cells respond to chemotherapeutic agents that damage DNA and interfere with the process of DNA repair.

What's next

Building on his findings, Dr. Cortez will continue to study these replication stress response pathways with an emphasis on defining how they determine the fate of cancer cells treated with PARP inhibitors, chemotherapeutic, and other agents. In ongoing work with his clinical colleagues, his team will also investigate drug combinations that can work to overcome PARP inhibitor resistance mechanisms.

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Learn more about Fergus J. Couch at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Fergus J. Couch | Researcher | Breast Cancer Research Foundation

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Learn more about Fergus J. Couch at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor of Laboratory Medicine And Pathology
Zbigniew and Anna M. Scheller Professor of Medical Research
Chair, Division of Experimental Pathology and Laboratory Medicine,
Department of Laboratory Medicine and Pathology

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Fergus Couch is Professor and Chair of the Division of Experimental Pathology and Laboratory Medicine at the Mayo Clinic, with joint appointments in the Departments of Health Sciences Research and Biochemistry and Molecular Biology. Dr. Couch works on the genetics of breast cancer, with over 300 publications relating to the discovery and clinical characterization of inherited genetic variants in cancer susceptibility genes.

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Fergus Couch is Professor and Chair of the Division of Experimental Pathology and Laboratory Medicine at the Mayo Clinic, with joint appointments in the Departments of Health Sciences Research and Biochemistry and Molecular Biology. Dr. Couch works on the genetics of breast cancer, with over 300 publications relating to the discovery and clinical characterization of inherited genetic variants in cancer susceptibility genes. He is the principal investigator of the Mayo Clinic Breast Cancer Registry and is a founder and a member of the coordinating committee of CIMBA (the consortium of investigators of modifiers of BRCA1/2) focused on identifying genetic modifiers of breast cancer risk in the BRCA1 carrier population. Similarly, he is the principal investigator of the Triple Negative Breast Cancer Consortium (TNBCC), aimed at understanding the genetic etiology of triple negative breast cancer, and is a long-term contributor to the international Breast Cancer Association Consortium (BCAC). Dr. Couch is a co-founder of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium focused on establishing the clinical relevance of variants of uncertain significance (VUS) in BRCA1/2. Within ENIGMA he is coordinating efforts to characterize the risk and penetrance of deleterious mutations and VUS in non-BRCA1/2 predisposition genes. He has also collaborated with investigators from Memorial Sloan Kettering Cancer Center and the University of Pennsylvania to develop the Prospective Registry Of Multi-Plex Testing (PROMPT) for patients with mutations in predisposition genes. Dr. Couch is a founding member and participant in COMPLEXO, a consortium aiming to identify additional breast cancer predisposition genes.

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Fergus Couch is Professor and Chair of the Division of Experimental Pathology and Laboratory Medicine at the Mayo Clinic, with joint appointments in the Departments of Health Sciences Research and Biochemistry and Molecular Biology. Dr. Couch works on the genetics of breast cancer, with over 300 publications relating to the discovery and clinical characterization of inherited genetic variants in cancer susceptibility genes. He is the principal investigator of the Mayo Clinic Breast Cancer Registry and is a founder and a member of the coordinating committee of CIMBA (the consortium of investigators of modifiers of BRCA1/2) focused on identifying genetic modifiers of breast cancer risk in the BRCA1 carrier population. Similarly, he is the principal investigator of the Triple Negative Breast Cancer Consortium (TNBCC), aimed at understanding the genetic etiology of triple negative breast cancer, and is a long-term contributor to the international Breast Cancer Association Consortium (BCAC). Dr. Couch is a co-founder of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium focused on establishing the clinical relevance of variants of uncertain significance (VUS) in BRCA1/2. Within ENIGMA he is coordinating efforts to characterize the risk and penetrance of deleterious mutations and VUS in non-BRCA1/2 predisposition genes. He has also collaborated with investigators from Memorial Sloan Kettering Cancer Center and the University of Pennsylvania to develop the Prospective Registry Of Multi-Plex Testing (PROMPT) for patients with mutations in predisposition genes. Dr. Couch is a founding member and participant in COMPLEXO, a consortium aiming to identify additional breast cancer predisposition genes.

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Goal: To improve risk prediction in women at high-risk of breast cancer.

Impact: Dr. Couch is conducting a series of studies to identify breast cancer predisposition genes and to estimate risk at all ages for those who have inherited mutations in these genes. His work may improve risk assessment in high-risk families and inform preventive intervention strategies.

What’s next: He and his colleagues will continue to refine breast cancer risks, resolve problematic mutations that have uncertain relevance to cancer, and identify new breast cancer genes that may account for the unexplained increased number of cancers in many families without known genetic factors.

BRCA1 and BRCA2 are the most well-known breast cancer risk genes, and women and men who inherit mutations in either gene have a significant risk of developing breast or other cancers. However, many other genes also increase the risk of breast cancer, but these are not fully understood. Dr. Couch aims to identify these genes and assess the risk they pose at various ages, which he hopes will lead to more accurate and informed risk management.​

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Goal: To improve risk prediction in women at high-risk of breast cancer.

Impact: Dr. Couch is conducting a series of studies to identify breast cancer predisposition genes and to estimate risk at all ages for those who have inherited mutations in these genes. His work may improve risk assessment in high-risk families and inform preventive intervention strategies.

What’s next: He and his colleagues will continue to refine breast cancer risks, resolve problematic mutations that have uncertain relevance to cancer, and identify new breast cancer genes that may account for the unexplained increased number of cancers in many families without known genetic factors.

BRCA1 and BRCA2 are the most well-known breast cancer risk genes, and women and men who inherit mutations in either gene have a significant risk of developing breast or other cancers. However, many other genes also increase the risk of breast cancer, but these are not fully understood. Dr. Couch aims to identify these genes and assess the risk they pose at various ages, which he hopes will lead to more accurate and informed risk management.​

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Research area: Identifying genes—beyond the well-known BRCA1 and BRCA2 genes—that increase the risk of breast cancer.

Impact: In addition to the BRCA genes, there are many other genes that when mutated predispose women and men to breast cancer. However, these are less well known, and even among those we do know, the risks of developing breast cancer at various ages are not well understood. As a result, many people at increased risk may not be identified or do not benefit from genetic testing of the known predisposition genes. Dr. Couch is conducting studies to fill in this information in order to improve risk assessment in high-risk families and spur new preventive intervention strategies.

Current investigation: He and his team have been developing estimates of cancer risks for inherited mutations found during clinical genetic testing. Through DNA sequencing, they will also identify new breast cancer genes which may be useful for identifying women at risk of developing breast cancer.

What he’s learned so far: Dr. Couch has provided the first-ever estimates of breast cancer risk for women of different races and ethnicities with inherited cancer predisposition gene mutations. Moreover, his team has shown that different types of breast cancer are caused by different genes. His team has also developed new methods to determine whether gene variants of uncertain significance are relevant to cancer risk. In preliminary studies, they have identified 21 new candidate genes which may be moderate-risk breast cancer susceptibility genes.

What’s next: Dr. Couch and his colleagues will use the methods they have developed to determine which gene variants of uncertain significance contribute to breast cancer risk. In addition, they will continue to characterize breast cancer risk associated with variants in known cancer predisposition genes as well as the new candidate moderate-risk genes. Lastly, his team will correlate expression of specific variants with patient response to endocrine agents and chemotherapy. The insights gained from these studies will lead to more informed, accurate, and beneficial risk management and guide therapy decisions for many women at increased risk of breast cancer.

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Research area: Identifying genes—beyond the well-known BRCA1 and BRCA2 genes—that increase the risk of breast cancer.

Impact: In addition to the BRCA genes, there are many other genes that when mutated predispose women and men to breast cancer. However, these are less well known, and even among those we do know, the risks of developing breast cancer at various ages are not well understood. As a result, many people at increased risk may not be identified or do not benefit from genetic testing of the known predisposition genes. Dr. Couch is conducting studies to fill in this information in order to improve risk assessment in high-risk families and spur new preventive intervention strategies.

Current investigation: He and his team have been developing estimates of cancer risks for inherited mutations found during clinical genetic testing. Through DNA sequencing, they will also identify new breast cancer genes which may be useful for identifying women at risk of developing breast cancer.

What he’s learned so far: Dr. Couch has provided the first-ever estimates of breast cancer risk for women of different races and ethnicities with inherited cancer predisposition gene mutations. Moreover, his team has shown that different types of breast cancer are caused by different genes. His team has also developed new methods to determine whether gene variants of uncertain significance are relevant to cancer risk. In preliminary studies, they have identified 21 new candidate genes which may be moderate-risk breast cancer susceptibility genes.

What’s next: Dr. Couch and his colleagues will use the methods they have developed to determine which gene variants of uncertain significance contribute to breast cancer risk. In addition, they will continue to characterize breast cancer risk associated with variants in known cancer predisposition genes as well as the new candidate moderate-risk genes. Lastly, his team will correlate expression of specific variants with patient response to endocrine agents and chemotherapy. The insights gained from these studies will lead to more informed, accurate, and beneficial risk management and guide therapy decisions for many women at increased risk of breast cancer.

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Professor of Laboratory Medicine And Pathology
Zbigniew and Anna M. Scheller Professor of Medical Research
Chair, Division of Experimental Pathology and Laboratory Medicine, 
Department of Laboratory Medicine and Pathology

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Identifying genes beyond the well-known BRCA1 and BRCA2 genes  that increase the risk of breast cancer to improve breast cancer risk prediction in women at high-risk.

Impact

Inherited breast cancer risk is most commonly associated with mutations in the BRCA1 and, to a lesser extent, BRCA2 genes. However, these are not the only established breast cancer susceptibility genes. Between seven and 10 percent of women with breast cancer are estimated to have mutations in breast cancer predisposition genes. But these estimates were based on studies of limited size and in high-risk populations. With early and sustained BCRF support, Dr. Couch and his colleagues undertook the CARRIERS (Cancer Risk Estimates Related to Susceptibility) study to examine genetic risk that could be applied to the general population, including African American, Asian, and Hispanic women. In this study, the team analyzed germline (inherited) DNA from 32,247 women with breast cancer and 32,544 unaffected women. They sought to answer two key questions: How frequently do mutations occur among genes, and can these gene mutations provide an accurate estimate of one’s risk of developing breast cancer? This is the first comprehensive study to examine the prevalence of inherited mutations in established breast cancer susceptibility genes. The insights gained from these studies will lead to more informed, accurate, and beneficial risk management and guide therapy decisions for many women at increased risk of breast cancer.

Progress Thus Far

Dr. Couch and his colleagues evaluated the frequency of mutations in 12 established predisposition genes, including BRCA1, BRCA2, PALB2, BARD1, and ATM. Mutations were detected in five percent of women with breast cancer, compared to 1.6 percent of unaffected women. Similar frequencies were observed among non-Hispanic white, African American, and Hispanic women. Not surprisingly, the highest frequency of mutations was observed in BRCA1 and BRCA2. Mutations in PALB2 were also correlated with moderate risk.

The researchers also correlated specific gene mutations with subtypes of breast cancer. Mutations on the BARD1, RAD51C, and RAD51D genes, while very uncommon, were associated with an increased risk of ER-negative and triple-negative breast cancer and were more frequent in African American women with breast cancer. Mutations in ATM, CDH1, and CHEK2 were linked to an increased risk of ER-positive breast cancer and more frequent in non-Hispanic white women—providing new insight into the racial difference in frequency of ER-negative versus ER-positive breast cancers.

What's next

Dr. Couch and his colleagues will continue to characterize breast cancer risk associated with variants in known cancer predisposition genes as well as the new candidate moderate-risk genes. In addition, they will continue their studies to determine which gene variants of uncertain significance contribute to breast cancer risk and  correlate expression of specific variants with patient response to endocrine agents and chemotherapy.

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Identifying genes beyond the well-known BRCA1 and BRCA2 genes  that increase the risk of breast cancer to improve breast cancer risk prediction in women at high-risk.

Impact

Inherited breast cancer risk is most commonly associated with mutations in the BRCA1 and, to a lesser extent, BRCA2 genes. However, these are not the only established breast cancer susceptibility genes. Between seven and 10 percent of women with breast cancer are estimated to have mutations in breast cancer predisposition genes. But these estimates were based on studies of limited size and in high-risk populations. With early and sustained BCRF support, Dr. Couch and his colleagues undertook the CARRIERS (Cancer Risk Estimates Related to Susceptibility) study to examine genetic risk that could be applied to the general population, including African American, Asian, and Hispanic women. In this study, the team analyzed germline (inherited) DNA from 32,247 women with breast cancer and 32,544 unaffected women. They sought to answer two key questions: How frequently do mutations occur among genes, and can these gene mutations provide an accurate estimate of one’s risk of developing breast cancer? This is the first comprehensive study to examine the prevalence of inherited mutations in established breast cancer susceptibility genes. The insights gained from these studies will lead to more informed, accurate, and beneficial risk management and guide therapy decisions for many women at increased risk of breast cancer.

Progress Thus Far

Dr. Couch and his colleagues evaluated the frequency of mutations in 12 established predisposition genes, including BRCA1, BRCA2, PALB2, BARD1, and ATM. Mutations were detected in five percent of women with breast cancer, compared to 1.6 percent of unaffected women. Similar frequencies were observed among non-Hispanic white, African American, and Hispanic women. Not surprisingly, the highest frequency of mutations was observed in BRCA1 and BRCA2. Mutations in PALB2 were also correlated with moderate risk.

The researchers also correlated specific gene mutations with subtypes of breast cancer. Mutations on the BARD1, RAD51C, and RAD51D genes, while very uncommon, were associated with an increased risk of ER-negative and triple-negative breast cancer and were more frequent in African American women with breast cancer. Mutations in ATM, CDH1, and CHEK2 were linked to an increased risk of ER-positive breast cancer and more frequent in non-Hispanic white women—providing new insight into the racial difference in frequency of ER-negative versus ER-positive breast cancers.

What's next

Dr. Couch and his colleagues will continue to characterize breast cancer risk associated with variants in known cancer predisposition genes as well as the new candidate moderate-risk genes. In addition, they will continue their studies to determine which gene variants of uncertain significance contribute to breast cancer risk and  correlate expression of specific variants with patient response to endocrine agents and chemotherapy.

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Learn more about Vincent L. Cryns at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Vincent L. Cryns | Researcher | Breast Cancer Research Foundation

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Learn more about Vincent L. Cryns at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Department of Medicine
Marian A. and Rodney P. Burgenske Chair,
Endocrinology, Diabetes & Metabolism

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Vincent Cryns, MD, is the Marian A. and Rodney P. Burgenske Chair in Diabetes Research and Chief, Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health. He received his bachelor’s and medical degrees from Harvard and completed subspecialty training in endocrinology at Massachusetts General Hospital. Before coming to Madison, Dr. Cryns was a Professor of Medicine at Northwestern University’s Feinberg School of Medicine.

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Vincent Cryns, MD, is the Marian A. and Rodney P. Burgenske Chair in Diabetes Research and Chief, Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health. He received his bachelor’s and medical degrees from Harvard and completed subspecialty training in endocrinology at Massachusetts General Hospital. Before coming to Madison, Dr. Cryns was a Professor of Medicine at Northwestern University’s Feinberg School of Medicine.

Dr. Cryns leads a multidisciplinary team that focuses on understanding how cells die. His group is especially interested in elucidating how abnormalities in cell death contribute to diseases such as cancer and obesity and in translating these insights into improved therapies. Dr. Cryns’ research is funded by the NIH, the Breast Cancer Research Foundation and other agencies. His work has been featured on National Public Radio’s "All Things Considered" and highlighted in Nature and Nature Reviews Cancer. Dr. Cryns has been the recipient of several awards, including an Outstanding Junior Faculty Award from the Avon Foundation, and he is an elected member of the American Society for Clinical Investigation.

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Vincent Cryns, MD, is the Marian A. and Rodney P. Burgenske Chair in Diabetes Research and Chief, Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health. He received his bachelor’s and medical degrees from Harvard and completed subspecialty training in endocrinology at Massachusetts General Hospital. Before coming to Madison, Dr. Cryns was a Professor of Medicine at Northwestern University’s Feinberg School of Medicine.

Dr. Cryns leads a multidisciplinary team that focuses on understanding how cells die. His group is especially interested in elucidating how abnormalities in cell death contribute to diseases such as cancer and obesity and in translating these insights into improved therapies. Dr. Cryns’ research is funded by the NIH, the Breast Cancer Research Foundation and other agencies. His work has been featured on National Public Radio’s "All Things Considered" and highlighted in Nature and Nature Reviews Cancer. Dr. Cryns has been the recipient of several awards, including an Outstanding Junior Faculty Award from the Avon Foundation, and he is an elected member of the American Society for Clinical Investigation.

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Goal: To improve outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.

Impact: Drs. Cryns and Gradishar are studying a cell stress protein called alphaβ-crystallin, which contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC). They have shown that it interacts with a mutant form of p53, the most commonly mutated gene in cancer, and links p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.

What’s next: The team will identify the specific role of alphaβ-crystallin in promoting tumor growth by common cancer-causing genes.

Basal-like tumors, which include those classified as triple negative, are aggressive and lack targeted therapies. Drs. Cryns and Gradishar have shown that a protein called alphaβ-crystallin contributes to the aggressive behavior of these tumors and regulates the spread of breast cancer to organs such as the brain. Recently, they discovered that alphaβ-crystallin binds to mutant p53 protein, promoting tumor growth. They have also discovered that this pathway links p53 and with a growth-promoting factor called Akt. The team will now study alphaβ-crystallin’s role in regulating these pathways.

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Goal: To improve outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.

Impact: Drs. Cryns and Gradishar are studying a cell stress protein called alphaβ-crystallin, which contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC). They have shown that it interacts with a mutant form of p53, the most commonly mutated gene in cancer, and links p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.

What’s next: The team will identify the specific role of alphaβ-crystallin in promoting tumor growth by common cancer-causing genes.

Basal-like tumors, which include those classified as triple negative, are aggressive and lack targeted therapies. Drs. Cryns and Gradishar have shown that a protein called alphaβ-crystallin contributes to the aggressive behavior of these tumors and regulates the spread of breast cancer to organs such as the brain. Recently, they discovered that alphaβ-crystallin binds to mutant p53 protein, promoting tumor growth. They have also discovered that this pathway links p53 and with a growth-promoting factor called Akt. The team will now study alphaβ-crystallin’s role in regulating these pathways.

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Research goal: Developing new approaches to treat aggressive breast cancers.

Impact: Basal-like triple negative breast cancers are aggressive and lack targeted therapies because they don’t depend on the estrogen or progesterone hormones or HER2 for growth, thus the term “triple-negative.” Drs. Cryns and Gradishar are investigating a cell stress protein called alphaβ-crystallin that contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by interacting with cancer-promoting proteins. Their findings may inform new targeted therapies that would prevent this protein from promoting metastasis.

Current investigation: The team is screening libraries of chemical compounds to identify drugs that block the interaction between alphaβ-crystallin and p53, the most commonly mutated gene in cancer. Alphaβ-crystallin binds directly to mutant p53 and keeps it active, thereby promoting tumor growth. Drugs that block the interaction between alphaβ-crystallin and p53 are predicted to cause tumor cell death.

What they’ve learned so far: Drs. Cryns and Gradishar showed that blocking alphaβ-crystallin binding to p53 prevents p53 from promoting tumor formation. They also discovered that this pathway directly links p53 and Akt, a potent growth factor.

What’s next: During the next year, the team will identify the specific role of alphaβ-crystallin in keeping p53 and Akt active and in promoting tumor growth by these genes.

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Research goal: Developing new approaches to treat aggressive breast cancers.

Impact: Basal-like triple negative breast cancers are aggressive and lack targeted therapies because they don’t depend on the estrogen or progesterone hormones or HER2 for growth, thus the term “triple-negative.” Drs. Cryns and Gradishar are investigating a cell stress protein called alphaβ-crystallin that contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by interacting with cancer-promoting proteins. Their findings may inform new targeted therapies that would prevent this protein from promoting metastasis.

Current investigation: The team is screening libraries of chemical compounds to identify drugs that block the interaction between alphaβ-crystallin and p53, the most commonly mutated gene in cancer. Alphaβ-crystallin binds directly to mutant p53 and keeps it active, thereby promoting tumor growth. Drugs that block the interaction between alphaβ-crystallin and p53 are predicted to cause tumor cell death.

What they’ve learned so far: Drs. Cryns and Gradishar showed that blocking alphaβ-crystallin binding to p53 prevents p53 from promoting tumor formation. They also discovered that this pathway directly links p53 and Akt, a potent growth factor.

What’s next: During the next year, the team will identify the specific role of alphaβ-crystallin in keeping p53 and Akt active and in promoting tumor growth by these genes.

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Professor, Department of Medicine 
Marian A. and Rodney P. Burgenske Chair,
Endocrinology, Diabetes & Metabolism 

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Improving outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.

Impact

Basal-like triple-negative breast cancers are aggressive and lack targeted therapies because they do not depend on the estrogen or progesterone hormones or HER2 for growth, hence the term “triple-negative.” Drs. Cryns and Gradishar are studying a cell stress protein called αβ-crystallin, which contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by interacting with cancer-promoting proteins. They have shown that it interacts with a mutant form of p53, the most commonly mutated gene in cancer, and links p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.

Progress Thus Far

The team has discovered that mutant p53 depends on αβ-crystallin to promote tumor formation. In addition, they identified a promising drug that reduces αβ-crystallin levels in breast cancer cells, and they plan to test this drug and related ones in TNBC models. Their findings could lead to completely new strategies to target and treat aggressive TNBC.

What's next

In the coming year, Drs. Cryns and Gradishar will focus on the mechanism by which αβ-crystallin promotes tumor growth using genetic tools. Their findings could lead to the identification of new approaches to target mutant p53 and/or αβ-crystallin, opening up a new treatment option for TNBC.

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Improving outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.

Impact

Basal-like triple-negative breast cancers are aggressive and lack targeted therapies because they do not depend on the estrogen or progesterone hormones or HER2 for growth, hence the term “triple-negative.” Drs. Cryns and Gradishar are studying a cell stress protein called αβ-crystallin, which contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by interacting with cancer-promoting proteins. They have shown that it interacts with a mutant form of p53, the most commonly mutated gene in cancer, and links p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.

Progress Thus Far

The team has discovered that mutant p53 depends on αβ-crystallin to promote tumor formation. In addition, they identified a promising drug that reduces αβ-crystallin levels in breast cancer cells, and they plan to test this drug and related ones in TNBC models. Their findings could lead to completely new strategies to target and treat aggressive TNBC.

What's next

In the coming year, Drs. Cryns and Gradishar will focus on the mechanism by which αβ-crystallin promotes tumor growth using genetic tools. Their findings could lead to the identification of new approaches to target mutant p53 and/or αβ-crystallin, opening up a new treatment option for TNBC.

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Learn more about Jack Cuzick at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Jack Cuzick | Researcher | Breast Cancer Research Foundation

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Learn more about Jack Cuzick at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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John Snow Professor of Epidemiology
Director, Wolfson Institute of Preventive Medicine
Head, Centre for Cancer Prevention

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on behalf of Australia and New Zealand Breast Cancer Trials Group

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Jack Cuzick, PhD is Director of the Wolfson Institute of Preventive Medicine in London. He is also head of the Centre for Cancer Prevention and John Snow Professor of Epidemiology at Queen Mary, University of London. He holds a PhD in Mathematics and has previously worked at Oxford University and Columbia University, New York.

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Jack Cuzick, PhD is Director of the Wolfson Institute of Preventive Medicine in London. He is also head of the Centre for Cancer Prevention and John Snow Professor of Epidemiology at Queen Mary, University of London. He holds a PhD in Mathematics and has previously worked at Oxford University and Columbia University, New York.

His current interests are in cancer epidemiology and clinical trials, with special interest in prevention and screening. He is currently Chairman of the International Breast Cancer Intervention Study (IBIS) Steering Group and the ATAC trial. He has worked extensively in breast cancer and was the first to report the effect of tamoxifen on contralateral tumors as an indicator of its potential chemopreventive role and also has demonstrated that a change in mammographic breast density on endocrine treatment is a biomarker for its effectiveness. He is involved in studies on the use of HPV assays for cervical screening, the use of flexible sigmoidoscopy for colorectal cancer screening and markers for the behavior of early prostate cancer.

Dr. Cuzick is a Fellow of the Academy of Medical Sciences, the Royal Statistical Society, the Institute of Mathematical Statistics, the Royal Society, and an Honorary Fellow of the Royal College of Physicians and was awarded a CBE by the Queen in 2017. In 2007, he was chosen by Thompson Scientific as one of the twelve hottest researchers in all of science and this has been re-awarded for several years thereafter. He was awarded the AACR Cancer Prevention Prize in 2012. He is the author of more than 650 peer-reviewed papers and has published in all the major medical journals

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Jack Cuzick, PhD is Director of the Wolfson Institute of Preventive Medicine in London. He is also head of the Centre for Cancer Prevention and John Snow Professor of Epidemiology at Queen Mary, University of London. He holds a PhD in Mathematics and has previously worked at Oxford University and Columbia University, New York.

His current interests are in cancer epidemiology and clinical trials, with special interest in prevention and screening. He is currently Chairman of the International Breast Cancer Intervention Study (IBIS) Steering Group and the ATAC trial. He has worked extensively in breast cancer and was the first to report the effect of tamoxifen on contralateral tumors as an indicator of its potential chemopreventive role and also has demonstrated that a change in mammographic breast density on endocrine treatment is a biomarker for its effectiveness. He is involved in studies on the use of HPV assays for cervical screening, the use of flexible sigmoidoscopy for colorectal cancer screening and markers for the behavior of early prostate cancer.

Dr. Cuzick is a Fellow of the Academy of Medical Sciences, the Royal Statistical Society, the Institute of Mathematical Statistics, the Royal Society, and an Honorary Fellow of the Royal College of Physicians and was awarded a CBE by the Queen in 2017. In 2007, he was chosen by Thompson Scientific as one of the twelve hottest researchers in all of science and this has been re-awarded for several years thereafter. He was awarded the AACR Cancer Prevention Prize in 2012. He is the author of more than 650 peer-reviewed papers and has published in all the major medical journals

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Goal: To identify protein and gene biomarkers that will improve risk assessment in women at high risk of developing breast cancer.

Impact: Drs. Cuzick and Francis are expanding their high-risk breast cancer biobank, which is a collection of blood and tissue samples, mammograms, and clinical data from women enrolled in breast cancer prevention and treatment trials. This resource will help them determine which types of breast cancer will respond to different kinds of preventive treatment.

What’s next: The team will collaborate with researchers around the world to collect samples and data from women taking part in several ongoing trials.

While large randomized clinical trials may provide clues for predicting response to therapy or late recurrence, the results don’t apply to every participant because individual responses are influenced by the patient’s and the tumor’s unique genetic profile. By gathering samples and data from women enrolled in clinical trials, Drs. Cuzick and Francis hope to identify biomarkers that will help them understand why some patients respond to therapy and others do not, and to identify patients at high risk of recurrence.

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Goal: To identify protein and gene biomarkers that will improve risk assessment in women at high risk of developing breast cancer.

Impact: Drs. Cuzick and Francis are expanding their high-risk breast cancer biobank, which is a collection of blood and tissue samples, mammograms, and clinical data from women enrolled in breast cancer prevention and treatment trials. This resource will help them determine which types of breast cancer will respond to different kinds of preventive treatment.

What’s next: The team will collaborate with researchers around the world to collect samples and data from women taking part in several ongoing trials.

While large randomized clinical trials may provide clues for predicting response to therapy or late recurrence, the results don’t apply to every participant because individual responses are influenced by the patient’s and the tumor’s unique genetic profile. By gathering samples and data from women enrolled in clinical trials, Drs. Cuzick and Francis hope to identify biomarkers that will help them understand why some patients respond to therapy and others do not, and to identify patients at high risk of recurrence.

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Research area: Seeking to improve breast cancer risk assessment in high-risk women by identifying protein and gene biomarkers.

Impact: Prevention research is a long-term game because it takes many years of follow-up to get a clear picture of the value of preventive therapy. This includes not only information on efficacy and side-effects, but also identifying biomarkers for predicting risk and response to treatment. The IBIS Prevention trials led by Dr. Cuzick continue to be the definitive studies on the preventive use of tamoxifen and the aromatase inhibitor anastrozole in women with a high risk of developing breast cancer. The High-Risk Breast Biobank (HRBCBB) was established as a repository for specimens from the IBIS trials with the goal to better understand who is at high risk of breast cancer, who will respond to endocrine (anti-estrogen) treatment—with a special interest in differential response to tamoxifen or aromatase inhibitor (anastrozole for these trials), and who is most likely to experience treatment-related side effects.

Current investigation: The team is expanding their High-Risk Breast Cancer Biobank (HRBCBB), which includes blood, tumor tissue, and mammograms, as well as clinical outcome data and long-term follow-up of individual women in prevention and treatment trials.

What they’ve learned so far: In the last year, Drs. Cuzick and Francis published results from IBIS II, a randomized, double-blind trial investigating the benefit of long-term anastrozole for the prevention of breast cancer in high-risk women. With a median follow up of five years, anastrozole significantly reduced breast cancer incidence, both invasive ductal carcinoma and ductal carcinoma in situ. These results were published in the journal, Lancet. They continue to follow patients to determine the impact of anastrozole on mortality.

What’s next: As new trials such as EXPERT, CHARIOT and DIAmOND are conducted and a new cohort study PRIMROSE is set up, biospecimens from participants in these investigations will be collected and added to the HRBCBB, further expanding this resource for future translational research.

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Research area: Seeking to improve breast cancer risk assessment in high-risk women by identifying protein and gene biomarkers.

Impact: Prevention research is a long-term game because it takes many years of follow-up to get a clear picture of the value of preventive therapy. This includes not only information on efficacy and side-effects, but also identifying biomarkers for predicting risk and response to treatment. The IBIS Prevention trials led by Dr. Cuzick continue to be the definitive studies on the preventive use of tamoxifen and the aromatase inhibitor anastrozole in women with a high risk of developing breast cancer. The High-Risk Breast Biobank (HRBCBB) was established as a repository for specimens from the IBIS trials with the goal to better understand who is at high risk of breast cancer, who will respond to endocrine (anti-estrogen) treatment—with a special interest in differential response to tamoxifen or aromatase inhibitor (anastrozole for these trials), and who is most likely to experience treatment-related side effects.

Current investigation: The team is expanding their High-Risk Breast Cancer Biobank (HRBCBB), which includes blood, tumor tissue, and mammograms, as well as clinical outcome data and long-term follow-up of individual women in prevention and treatment trials.

What they’ve learned so far: In the last year, Drs. Cuzick and Francis published results from IBIS II, a randomized, double-blind trial investigating the benefit of long-term anastrozole for the prevention of breast cancer in high-risk women. With a median follow up of five years, anastrozole significantly reduced breast cancer incidence, both invasive ductal carcinoma and ductal carcinoma in situ. These results were published in the journal, Lancet. They continue to follow patients to determine the impact of anastrozole on mortality.

What’s next: As new trials such as EXPERT, CHARIOT and DIAmOND are conducted and a new cohort study PRIMROSE is set up, biospecimens from participants in these investigations will be collected and added to the HRBCBB, further expanding this resource for future translational research.

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John Snow Professor of Epidemiology 
Director, Wolfson Institute of Preventive Medicine
Head, Centre for Cancer Prevention

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Improving risk and prognostic assessments for breast cancer.

Impact

Analysis of biobanked samples—blood, tissue, and clinical data from consenting patients—is a critical component of all cancer research. Mountains of data can be gleaned from these samples, whether it’s looking for patterns that can predict breast cancer risk or maximizing the amount of information gathered from a clinical trial. The IBIS Prevention trials, led by Dr. Cuzick and retired colleague Dr. John Forbes, began in 1992 and continue to be the definitive studies on the use of tamoxifen and anastrozole in patients with a high risk of developing breast cancer. Today, Drs. Cuzick and Francis’ studies help guide the most appropriate screening and preventative strategies for individuals based on better estimates of their breast cancer risk.

Progress Thus Far

Prevention research is a long-term game because it takes many years of follow-up to get a clear picture of the value of preventive therapy. The High-Risk Breast Cancer Biobank (HRBCBB) was established as a repository for specimens from the IBIS trials to better understand who is at high risk of breast cancer, who will respond to treatment, and who is most likely to experience treatment-related side effects. Using the material collected in the HRBCBB, the team carried out the first biomarker studies in a ductal carcinoma in situ (DCIS) randomized trial evaluating the prognostic role of the breast cancer genes estrogen receptor (ER) and HER2. They confirmed the prognostic role of ER and HER2 in DCIS—i.e., they are markers that can help stratify patients as either high or low risk of recurrence. Furthermore, they found that HER2 also predicted radiotherapy benefit, thereby helping in treatment decisions.

What’s next

Ongoing analyses by the team include studying the IBIS-II prevention trial to see if a patient’s natural hormone levels affect the performance of preventative therapies in high-risk individuals. They also are examining the role of mutations for more than 100 genes in cancer tissues in the TransATAC cohort. In addition, the team will collaborate with researchers around the world to collect data from several ongoing therapeutic trials. The EXPERT clinical trial is a radiation oncology “equivalent” of the TAILORx trial—utilizing a multigene assay to see if radiation therapy can be safely de-escalated in the context of adjuvant endocrine therapy. Correlative studies using  biobanked clinical samples from immunotherapy trials such as DIAmOND, and Neo-N, led by BCRF investigator Sherene Loi, provide opportunities to tailor immunotherapy to those patients most likely to benefit.

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Improving risk and prognostic assessments for breast cancer.

Impact

Analysis of biobanked samples—blood, tissue, and clinical data from consenting patients—is a critical component of all cancer research. Mountains of data can be gleaned from these samples, whether it’s looking for patterns that can predict breast cancer risk or maximizing the amount of information gathered from a clinical trial. The IBIS Prevention trials, led by Dr. Cuzick and retired colleague Dr. John Forbes, began in 1992 and continue to be the definitive studies on the use of tamoxifen and anastrozole in patients with a high risk of developing breast cancer. Today, Drs. Cuzick and Francis’ studies help guide the most appropriate screening and preventative strategies for individuals based on better estimates of their breast cancer risk.

Progress Thus Far

Prevention research is a long-term game because it takes many years of follow-up to get a clear picture of the value of preventive therapy. The High-Risk Breast Cancer Biobank (HRBCBB) was established as a repository for specimens from the IBIS trials to better understand who is at high risk of breast cancer, who will respond to treatment, and who is most likely to experience treatment-related side effects. Using the material collected in the HRBCBB, the team carried out the first biomarker studies in a ductal carcinoma in situ (DCIS) randomized trial evaluating the prognostic role of the breast cancer genes estrogen receptor (ER) and HER2. They confirmed the prognostic role of ER and HER2 in DCIS—i.e., they are markers that can help stratify patients as either high or low risk of recurrence. Furthermore, they found that HER2 also predicted radiotherapy benefit, thereby helping in treatment decisions.

What’s next

Ongoing analyses by the team include studying the IBIS-II prevention trial to see if a patient’s natural hormone levels affect the performance of preventative therapies in high-risk individuals. They also are examining the role of mutations for more than 100 genes in cancer tissues in the TransATAC cohort. In addition, the team will collaborate with researchers around the world to collect data from several ongoing therapeutic trials. The EXPERT clinical trial is a radiation oncology “equivalent” of the TAILORx trial—utilizing a multigene assay to see if radiation therapy can be safely de-escalated in the context of adjuvant endocrine therapy. Correlative studies using  biobanked clinical samples from immunotherapy trials such as DIAmOND, and Neo-N, led by BCRF investigator Sherene Loi, provide opportunities to tailor immunotherapy to those patients most likely to benefit.

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Learn more about Alan D'Andrea at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Alan D'Andrea | Researcher | Breast Cancer Research Foundation

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Learn more about Alan D'Andrea at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Alvan T. and Viola D. Fuller-American Cancer Society Professor
Radiation Oncology
Scientific Director, Molecular Diagnostics Laboratory
Harvard Medical School

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Early in his career, Alan D’Andrea, MD began to study the molecular pathogenesis of Fanconi Anemia (FA), a human genetic disease characterized by bone marrow failure, cancer susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Dr. D’Andrea’s laboratory contributed significantly to the elucidation of a new DNA repair pathway, the FA pathway, and demonstrated that one of the FA genes (FANCD1) is identical to the breast cancer gene, BRCA2.

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Early in his career, Alan D’Andrea, MD began to study the molecular pathogenesis of Fanconi Anemia (FA), a human genetic disease characterized by bone marrow failure, cancer susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Dr. D’Andrea’s laboratory contributed significantly to the elucidation of a new DNA repair pathway, the FA pathway, and demonstrated that one of the FA genes (FANCD1) is identical to the breast cancer gene, BRCA2. Biomarkers from this pathway are useful in predicting the chemotherapy and radiation sensitivity of breast, gastrointestinal, ovarian, and lung tumors.

Dr. D’Andrea is internationally known for his research in the area of DNA damage and DNA repair. He is currently the Fuller-American Cancer Society Professor of Radiation Oncology at Harvard Medical School and the Director of the Center for DNA Damage and Repair at the Dana-Farber Cancer Institute. A recipient of numerous academic awards, Dr. D’Andrea is a Distinguished Clinical Investigator of the Doris Duke Charitable Trust, and a Fellow of the American Association for the Advancement of Science. He is the recipient of the 2001 E. Mead Johnson Award, the highest award in Pediatric Research, and the 2012 G.H.A. Clowes Memorial Award from the American Association for Cancer Research. He is also a member of the National Cancer Institute's Board of Scientific Counselors in Basic Sciences.

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Early in his career, Alan D’Andrea, MD began to study the molecular pathogenesis of Fanconi Anemia (FA), a human genetic disease characterized by bone marrow failure, cancer susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Dr. D’Andrea’s laboratory contributed significantly to the elucidation of a new DNA repair pathway, the FA pathway, and demonstrated that one of the FA genes (FANCD1) is identical to the breast cancer gene, BRCA2. Biomarkers from this pathway are useful in predicting the chemotherapy and radiation sensitivity of breast, gastrointestinal, ovarian, and lung tumors.

Dr. D’Andrea is internationally known for his research in the area of DNA damage and DNA repair. He is currently the Fuller-American Cancer Society Professor of Radiation Oncology at Harvard Medical School and the Director of the Center for DNA Damage and Repair at the Dana-Farber Cancer Institute. A recipient of numerous academic awards, Dr. D’Andrea is a Distinguished Clinical Investigator of the Doris Duke Charitable Trust, and a Fellow of the American Association for the Advancement of Science. He is the recipient of the 2001 E. Mead Johnson Award, the highest award in Pediatric Research, and the 2012 G.H.A. Clowes Memorial Award from the American Association for Cancer Research. He is also a member of the National Cancer Institute's Board of Scientific Counselors in Basic Sciences.

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Research Area: To identify novel strategies to sensitize triple-negative breast cancers to treatment with PARP inhibitors.

Impact: Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). PARP inhibitors are helpful for the treatment of some TNBCs that have an underlying defect in DNA repair. However, after initially responding to this treatment, TNBC tumors often acquire resistance. There is a lack of additional therapies available for PARP inhibitor resistant tumors. Therefore, Dr. D’Andrea is developing ways to extend the use of PARP inhibitors for the treatment of TNBC patients. He hopes to discover novel combinations of drugs or methods to sensitize tumors to PARP inhibitors thereby increasing their efficacy and decreasing treatment resistance.

Progress Thus Far: Dr. D'Andrea and his colleagues have shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They have also identified two drug targets which they have shown contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP inhibitor resistance and re-sensitize the tumor cells to the drug.  With BCRF support, Dr. D’Andrea has successfully demonstrated that the naturally occuring antibiotic, novobiocin, effectively kills TNBC tumors in laboratory models.

What's next: Dr. D’ Andrea and his colleagues will continue to investigate novobiocin and other agents that can kill tumors that have become resistant PARP inhibitors.  In the coming year, his team will initiate a phase 1 clinical trial to test the combination of  novobiocin with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors.

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Research Area: To identify novel strategies to sensitize triple-negative breast cancers to treatment with PARP inhibitors.

Impact: Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). PARP inhibitors are helpful for the treatment of some TNBCs that have an underlying defect in DNA repair. However, after initially responding to this treatment, TNBC tumors often acquire resistance. There is a lack of additional therapies available for PARP inhibitor resistant tumors. Therefore, Dr. D’Andrea is developing ways to extend the use of PARP inhibitors for the treatment of TNBC patients. He hopes to discover novel combinations of drugs or methods to sensitize tumors to PARP inhibitors thereby increasing their efficacy and decreasing treatment resistance.

Progress Thus Far: Dr. D'Andrea and his colleagues have shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They have also identified two drug targets which they have shown contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP inhibitor resistance and re-sensitize the tumor cells to the drug.  With BCRF support, Dr. D’Andrea has successfully demonstrated that the naturally occuring antibiotic, novobiocin, effectively kills TNBC tumors in laboratory models.

What's next: Dr. D’ Andrea and his colleagues will continue to investigate novobiocin and other agents that can kill tumors that have become resistant PARP inhibitors.  In the coming year, his team will initiate a phase 1 clinical trial to test the combination of  novobiocin with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors.

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Research goal: Developing combination approaches that improve response to a class of drugs called PARP- inhibitors that are used to treat triple-negative breast cancer.

Impact: Triple-negative breast cancer (TNBC) is an especially aggressive form of breast cancer that is highly prone to metastasis. Studies indicate that a new class of drugs, called PARP-inhibitors, are useful for the treatment of some TNBCs—namely, those with an underlying defect in a DNA repair mechanism, called homologous recombination (HR) repair. HR defects are frequently observed in TNBC. While TNBC patients may respond initially to PARP-inhibitor treatment, these tumors often acquire resistance and there is currently no therapy available for PARP-inhibitor resistant tumors. Dr. D’Andrea’s work is aimed at identifying strategies to prevent resistance to PARP inhibitors and extend their use to more patients.

Current investigation: Confirming that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors – this will set the stage for a phase 1 clinical trial to test the combination of Novobiocin plus PARP-inhibitor for treating TNBC patients.

What he’s learned so far: Dr. D’Andrea and his colleagues have shown that combining PARP-inhibitors with drugs that block a certain kind of DNA repair (HR repair) can strongly extend their efficacy and are particularly useful for treating TNBC. Specifically, they have demonstrated that the CDK1 inhibitor, dinaciclib, and the PI3 kinase inhibitor, BYL719, are capable of blocking HR repair and sensitizing TNBC tumor cells to PARP-inhibitors. They have identified two drug targets which appear to contribute to the aggressive behavior and PARP-inhibitor resistance of some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP-inhibitor resistance and re-sensitize the tumor cells to PARP-inhibitor. Moreover, they have identified a specific inhibitor of POLQ, Novobiocin.

What’s next: Dr. D’Andrea and his colleagues will continue to test drug combinations in laboratory models of TNBC. His team will confirm that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors. The results of these studies will support initiation of a phase 1 clinical trial to test drug combinations for treating TNBC patients, including the combination of Novobiocin plus PARP-inhibitor.

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Research goal: Developing combination approaches that improve response to a class of drugs called PARP- inhibitors that are used to treat triple-negative breast cancer.

Impact: Triple-negative breast cancer (TNBC) is an especially aggressive form of breast cancer that is highly prone to metastasis. Studies indicate that a new class of drugs, called PARP-inhibitors, are useful for the treatment of some TNBCs—namely, those with an underlying defect in a DNA repair mechanism, called homologous recombination (HR) repair. HR defects are frequently observed in TNBC. While TNBC patients may respond initially to PARP-inhibitor treatment, these tumors often acquire resistance and there is currently no therapy available for PARP-inhibitor resistant tumors. Dr. D’Andrea’s work is aimed at identifying strategies to prevent resistance to PARP inhibitors and extend their use to more patients.

Current investigation: Confirming that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors – this will set the stage for a phase 1 clinical trial to test the combination of Novobiocin plus PARP-inhibitor for treating TNBC patients.

What he’s learned so far: Dr. D’Andrea and his colleagues have shown that combining PARP-inhibitors with drugs that block a certain kind of DNA repair (HR repair) can strongly extend their efficacy and are particularly useful for treating TNBC. Specifically, they have demonstrated that the CDK1 inhibitor, dinaciclib, and the PI3 kinase inhibitor, BYL719, are capable of blocking HR repair and sensitizing TNBC tumor cells to PARP-inhibitors. They have identified two drug targets which appear to contribute to the aggressive behavior and PARP-inhibitor resistance of some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP-inhibitor resistance and re-sensitize the tumor cells to PARP-inhibitor. Moreover, they have identified a specific inhibitor of POLQ, Novobiocin.

What’s next: Dr. D’Andrea and his colleagues will continue to test drug combinations in laboratory models of TNBC. His team will confirm that a POLQ inhibitor, Novobiocin, and/or a novel TRIP13 inhibitor, can kill PARP-inhibitor resistant tumors. The results of these studies will support initiation of a phase 1 clinical trial to test drug combinations for treating TNBC patients, including the combination of Novobiocin plus PARP-inhibitor.

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Alvan T. and Viola D. Fuller-American Cancer Society Professor
Radiation Oncology
Scientific Director, Molecular Diagnostics Laboratory
Harvard Medical School

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To identify novel strategies to sensitize triple-negative breast cancers to treatment with PARP inhibitors.

Impact

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). PARP inhibitors are helpful for the treatment of some TNBCs that have an underlying defect in DNA repair. However, after initially responding to this treatment, TNBC tumors often acquire resistance. There is a lack of additional therapies available for PARP inhibitor resistant tumors. Therefore, Dr. D’Andrea is developing ways to extend the use of PARP inhibitors for the treatment of TNBC patients. He hopes to discover novel combinations of drugs or methods to sensitize tumors to PARP inhibitors thereby increasing their efficacy and decreasing treatment resistance.

Progress Thus Far

Dr. D'Andrea and his colleagues have shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They have also identified two drug targets that  contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP inhibitor resistance and re-sensitize the tumor cells to the drug. With BCRF support, Dr. D’Andrea has successfully demonstrated that the naturally occurring antibiotic, novobiocin (NVB), effectively kills TNBC tumors in laboratory models. Building on these findings, they tested the drug in combination with PARP inhibitors and showed that NVB is strongly synergistic with PARP inhibitors especially in tumors that have compromised DNA repair. This combination was also shown to overcome PARP inhibitor resistance in laboratory models. Dr. D’Andrea and his team identified several biomarkers that predict whether tumor cells will be sensitive to NVB. In order to test these results in the clinic, they designed a clinical trial that will begin accrual in 2022.

What's next

Dr. D’ Andrea' team will initiate a phase I clinical trial to test the combination of NVB with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors. The identified biomarkers will be assessed for their utility in predicting which tumors will respond to NVB and if validated will be utilized to enroll patients in the clinical trial who are most likely to respond to NVB. Further laboratory studies will examine the mechanism underlying the interaction of NVB and PARP inhibitors, as well as test their activity with and without immune checkpoint blockade therapies. Together, these studies will provide tools to potentially increase the utility of PARP inhibitors for patients with aggressive TNBC.

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To identify novel strategies to sensitize triple-negative breast cancers to treatment with PARP inhibitors.

Impact

Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that is highly prone to metastasis (spreading to distant tissues). PARP inhibitors are helpful for the treatment of some TNBCs that have an underlying defect in DNA repair. However, after initially responding to this treatment, TNBC tumors often acquire resistance. There is a lack of additional therapies available for PARP inhibitor resistant tumors. Therefore, Dr. D’Andrea is developing ways to extend the use of PARP inhibitors for the treatment of TNBC patients. He hopes to discover novel combinations of drugs or methods to sensitize tumors to PARP inhibitors thereby increasing their efficacy and decreasing treatment resistance.

Progress Thus Far

Dr. D'Andrea and his colleagues have shown that combining PARP inhibitors with other targeted drugs that also block DNA repair can sensitize TNBC tumor cells to PARP inhibitors. They have also identified two drug targets that  contribute to the aggressive behavior and resistance to PARP inhibitors in some TNBCs: TRIP13 and POLQ. Preliminary data from TNBC laboratory models indicates that inhibitors of these targets can overcome PARP inhibitor resistance and re-sensitize the tumor cells to the drug. With BCRF support, Dr. D’Andrea has successfully demonstrated that the naturally occurring antibiotic, novobiocin (NVB), effectively kills TNBC tumors in laboratory models. Building on these findings, they tested the drug in combination with PARP inhibitors and showed that NVB is strongly synergistic with PARP inhibitors especially in tumors that have compromised DNA repair. This combination was also shown to overcome PARP inhibitor resistance in laboratory models. Dr. D’Andrea and his team identified several biomarkers that predict whether tumor cells will be sensitive to NVB. In order to test these results in the clinic, they designed a clinical trial that will begin accrual in 2022.

What's next

Dr. D’ Andrea' team will initiate a phase I clinical trial to test the combination of NVB with PARP inhibitors in patients with TNBC tumors that are resistant to PARP inhibitors. The identified biomarkers will be assessed for their utility in predicting which tumors will respond to NVB and if validated will be utilized to enroll patients in the clinical trial who are most likely to respond to NVB. Further laboratory studies will examine the mechanism underlying the interaction of NVB and PARP inhibitors, as well as test their activity with and without immune checkpoint blockade therapies. Together, these studies will provide tools to potentially increase the utility of PARP inhibitors for patients with aggressive TNBC.

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Learn more about Sandra Demaria at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Sandra Demaria | Researcher | Breast Cancer Research Foundation

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Learn more about Sandra Demaria at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor, Radiation Oncology<br />
Professor, Pathology and Laboratory Medicine

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Sandra Demaria, MD, a native of Turin, Italy, obtained her MD from the University of Turin. She then moved to New York City for her post-doctoral training in immunology as a Damon Runyon-Walter Winchell Cancer Research Fund awardee, followed by a residency in anatomic pathology at New York University School of Medicine. She remained on the faculty at NYU School of Medicine, where she was an attending pathologist in the breast cancer service, an independent investigator and co-leader of the Cancer Immunology program of NYU Cancer Institute until 2015, raising to the rank of Professor.

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Sandra Demaria, MD, a native of Turin, Italy, obtained her MD from the University of Turin. She then moved to New York City for her post-doctoral training in immunology as a Damon Runyon-Walter Winchell Cancer Research Fund awardee, followed by a residency in anatomic pathology at New York University School of Medicine. She remained on the faculty at NYU School of Medicine, where she was an attending pathologist in the breast cancer service, an independent investigator and co-leader of the Cancer Immunology program of NYU Cancer Institute until 2015, raising to the rank of Professor. She is currently Professor of Radiation Oncology and Pathology at Weill Cornell Medicine Medical College where she leads a NIH-funded laboratory. 

Dr. Demaria is internationally known for her studies demonstrating the synergy of local radiation therapy with different immunotherapeutic agents in pre-clinical models of cancer. She was the first to show that radiotherapy can convert breast tumors unresponsive to immune checkpoint inhibitors into responsive ones. She has been working in partnership with Dr. Silvia Formenti for the past decade to develop a novel treatment paradigm exploiting the immune adjuvant effects of radiotherapy and translate the pre-clinical findings to the clinic. 

Dr. Demaria's current work is aimed at identifying the molecular mechanisms that regulate ionizing radiation’s ability to generate an in situ tumor vaccine in preclinical tumor models as well as cancer patients treated in clinical trials testing various combinations of radiation and immunotherapy. As a breast cancer pathologist, Dr. Demaria has also studied the immunological microenvironment of breast cancer in patients, and therapeutic strategies to modulate the immune infiltrate in preclinical breast cancer models. 

She holds leadership positions in national professional societies, including the Society for Immunotherapy of Cancer (SITC) where she currently serves on the Board, and is a member of the Steering Committee of AACR Cancer Immunology Working Group. She is also an elected member of the European Academy for Tumor Immunology (EATI), and serves in the editorial board of several journals, including Radiation Research, The Journal of Immunology, Clinical Cancer Research, and Journal for ImmunoTherapy of Cancer. 

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Sandra Demaria, MD, a native of Turin, Italy, obtained her MD from the University of Turin. She then moved to New York City for her post-doctoral training in immunology as a Damon Runyon-Walter Winchell Cancer Research Fund awardee, followed by a residency in anatomic pathology at New York University School of Medicine. She remained on the faculty at NYU School of Medicine, where she was an attending pathologist in the breast cancer service, an independent investigator and co-leader of the Cancer Immunology program of NYU Cancer Institute until 2015, raising to the rank of Professor. She is currently Professor of Radiation Oncology and Pathology at Weill Cornell Medicine Medical College where she leads a NIH-funded laboratory.

Dr. Demaria is internationally known for her studies demonstrating the synergy of local radiation therapy with different immunotherapeutic agents in pre-clinical models of cancer. She was the first to show that radiotherapy can convert breast tumors unresponsive to immune checkpoint inhibitors into responsive ones. She has been working in partnership with Dr. Silvia Formenti for the past decade to develop a novel treatment paradigm exploiting the immune adjuvant effects of radiotherapy and translate the pre-clinical findings to the clinic.

Dr. Demaria's current work is aimed at identifying the molecular mechanisms that regulate ionizing radiation’s ability to generate an in situ tumor vaccine in preclinical tumor models as well as cancer patients treated in clinical trials testing various combinations of radiation and immunotherapy. As a breast cancer pathologist, Dr. Demaria has also studied the immunological microenvironment of breast cancer in patients, and therapeutic strategies to modulate the immune infiltrate in preclinical breast cancer models.

She holds leadership positions in national professional societies, including the Society for Immunotherapy of Cancer (SITC) where she currently serves on the Board, and is a member of the Steering Committee of AACR Cancer Immunology Working Group. She is also an elected member of the European Academy for Tumor Immunology (EATI), and serves in the editorial board of several journals, including Radiation Research, The Journal of Immunology, Clinical Cancer Research, and Journal for ImmunoTherapy of Cancer.

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Goal: To improve response to immune-based therapies so that more patients can benefit from this promising treatment.

Impact: A new class of cancer immunotherapy drugs called checkpoint inhibitors have shown promise in several cancers including some breast cancers. Unfortunately, few breast cancer patients have benefitted thus far. Drs. Demaria and Formenti are investigating ways to improve response to immunotherapies such as checkpoint inhibitor (CPI) therapy with radiation treatment. This innovative approach can potentially make immunotherapy a successful and durable treatment approach for breast cancer patients.

What’s next: Having discovered that radiotherapy not only kills tumor cells but also recruits the immune system by triggering signals that mimic an infection, Drs. Demaria and Formenti will determine how to optimize the use of radiotherapy with immunotherapy to improve patient outcome.

Treatments that harness the power of the immune system to fight cancer can be very effective, but most breast cancer patients do not respond to the current immunotherapy with checkpoint inhibitors. Drs. Demaria and Formenti are studying the efficacy of combining immunotherapy with radiotherapy, which they have found has the potential to convert a tumor that is not responsive to immunotherapy into a responsive one.

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Goal: To improve response to immune-based therapies so that more patients can benefit from this promising treatment.

Impact: A new class of cancer immunotherapy drugs called checkpoint inhibitors have shown promise in several cancers including some breast cancers. Unfortunately, few breast cancer patients have benefitted thus far. Drs. Demaria and Formenti are investigating ways to improve response to immunotherapies such as checkpoint inhibitor (CPI) therapy with radiation treatment. This innovative approach can potentially make immunotherapy a successful and durable treatment approach for breast cancer patients.

What’s next: Having discovered that radiotherapy not only kills tumor cells but also recruits the immune system by triggering signals that mimic an infection, Drs. Demaria and Formenti will determine how to optimize the use of radiotherapy with immunotherapy to improve patient outcome.

Treatments that harness the power of the immune system to fight cancer can be very effective, but most breast cancer patients do not respond to the current immunotherapy with checkpoint inhibitors. Drs. Demaria and Formenti are studying the efficacy of combining immunotherapy with radiotherapy, which they have found has the potential to convert a tumor that is not responsive to immunotherapy into a responsive one.

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Research area: Identifying ways to improve response to immunotherapy in breast cancer patients.

Impact: Immunotherapy—a type of treatment that stimulates a person’s immune system to recognize and destroy cancer cells—is a promising form of treatment. Checkpoint inhibitors (CPI) are a new calls of immunotherapy agents that work by preventing tumor cells from shutting down tumor immune response. Several CPI drugs are approved for treatment of various types of cancers, including some breast cancers, however, their effectiveness in breast cancer has been disappointing overall. Research by Drs. Demaria and Formenti has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into responsive (immunogenically hot) one.

Current investigation: The team has developed a platform to study the immunogenic effects of radiotherapy. They will use this platform to examine individual patients’ tumors to determine the tumor factors that mediate an optimal response to radiotherapy.

What they’ve learned so far: Drs. Demaria and Formenti have shown that radiotherapy may convert a tumor that is unresponsive to immunotherapy – sometimes referred to as a “cold” tumor – into a responsive “hot” one. It does this by generating T cells, the cancer-fighting cells of the immune system. Testing in laboratory models has revealed that it is possible to optimize the dose of radiotherapy to achieve this effect. In the last year, Drs. Demaria and Formenti have developed patient-derived tumor organoids from different types of breast cancers. This approach allows them to study the response of breast tumors to different doses of radiotherapy in the laboratory.

What’s next: The team will utilize patient-derived tumor organoids to optimize radiotherapy doses and to study radiation induced pro-immunogenic responses that occur in irradiated tumors. They will also study how circulating exosomes can be used as biomarkers of radiotherapy-induced pro-immunogenic responses. These studies provide a critical step towards developing precision radiotherapy and determining how it can be used to enhance response to immunotherapy.

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Research area: Identifying ways to improve response to immunotherapy in breast cancer patients.

Impact: Immunotherapy—a type of treatment that stimulates a person’s immune system to recognize and destroy cancer cells—is a promising form of treatment. Checkpoint inhibitors (CPI) are a new calls of immunotherapy agents that work by preventing tumor cells from shutting down tumor immune response. Several CPI drugs are approved for treatment of various types of cancers, including some breast cancers, however, their effectiveness in breast cancer has been disappointing overall. Research by Drs. Demaria and Formenti has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into responsive (immunogenically hot) one.

Current investigation: The team has developed a platform to study the immunogenic effects of radiotherapy. They will use this platform to examine individual patients’ tumors to determine the tumor factors that mediate an optimal response to radiotherapy.

What they’ve learned so far: Drs. Demaria and Formenti have shown that radiotherapy may convert a tumor that is unresponsive to immunotherapy – sometimes referred to as a “cold” tumor – into a responsive “hot” one. It does this by generating T cells, the cancer-fighting cells of the immune system. Testing in laboratory models has revealed that it is possible to optimize the dose of radiotherapy to achieve this effect. In the last year, Drs. Demaria and Formenti have developed patient-derived tumor organoids from different types of breast cancers. This approach allows them to study the response of breast tumors to different doses of radiotherapy in the laboratory.

What’s next: The team will utilize patient-derived tumor organoids to optimize radiotherapy doses and to study radiation induced pro-immunogenic responses that occur in irradiated tumors. They will also study how circulating exosomes can be used as biomarkers of radiotherapy-induced pro-immunogenic responses. These studies provide a critical step towards developing precision radiotherapy and determining how it can be used to enhance response to immunotherapy.

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Professor, Radiation Oncology
Professor, Pathology and Laboratory Medicine 

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Identifying ways to improve response to immunotherapy so that more patients can benefit from this promising treatment.

Impact

Immunotherapy stimulates a person's immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer patients. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy, work by preventing tumor cells from evading a patient’s immune response. While CPI drugs are approved for treatment of various types of cancers, including some breast cancers, their effectiveness in breast cancer has been disappointing overall. Drs. Demaria and Formenti are investigating ways to improve response to immunotherapies by combining it with radiation treatment. Their research has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into a responsive (immunogenically hot) one.  It does this by generating T cells, the cancer-fighting cells of the immune system. Drs. Demaria and Formenti have taken cells from patients with different types of breast cancer and developed a series of laboratory models that recapitulate the 3D environment of the tumors. Using these innovative models, they will determine ways to enhance responses to immunotherapy with radiation—this will provide a critical step towards developing precision radiotherapy, facilitating its use in combination with immunotherapy as a successful and durable treatment approach for breast cancer patients.

Progress Thus Far

Drs. Demaria and Formenti have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight the cancer. They have found that hormone receptor-positive and triple-negative breast cancers (TNBCs) activate different inflammatory pathways in response to radiation. In the last year, they identified several genes that are significantly upregulated by radiation in both subtypes and these genes serve important roles in the cross-talk between breast cancer cells and immune cells. In addition, they have characterized their 3D models and and obtained characterized long-term 3D models of TNBC. These models provide unique vehicles for further in-depth investigations to optimize the combination of radiation and CPI therapy, tailoring the treatment to specific characteristics of each tumor.

What's next

In the coming year, Drs. Demaria and Formenti will continue to examine how the molecular subtype of breast cancer affects the ability of radiation therapy to induce the immune signals required for an anti-tumor response. Ongoing studies will continue to examine the genes identified in the last year.  They will also leverage the information derived from their model systems to perform pre-clinical studies to determine ways to monitor an immunogenic response to tumor irradiation.

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Identifying ways to improve response to immunotherapy so that more patients can benefit from this promising treatment.

Impact

Immunotherapy stimulates a person's immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer patients. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy, work by preventing tumor cells from evading a patient’s immune response. While CPI drugs are approved for treatment of various types of cancers, including some breast cancers, their effectiveness in breast cancer has been disappointing overall. Drs. Demaria and Formenti are investigating ways to improve response to immunotherapies by combining it with radiation treatment. Their research has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into a responsive (immunogenically hot) one.  It does this by generating T cells, the cancer-fighting cells of the immune system. Drs. Demaria and Formenti have taken cells from patients with different types of breast cancer and developed a series of laboratory models that recapitulate the 3D environment of the tumors. Using these innovative models, they will determine ways to enhance responses to immunotherapy with radiation—this will provide a critical step towards developing precision radiotherapy, facilitating its use in combination with immunotherapy as a successful and durable treatment approach for breast cancer patients.

Progress Thus Far

Drs. Demaria and Formenti have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight the cancer. They have found that hormone receptor-positive and triple-negative breast cancers (TNBCs) activate different inflammatory pathways in response to radiation. In the last year, they identified several genes that are significantly upregulated by radiation in both subtypes and these genes serve important roles in the cross-talk between breast cancer cells and immune cells. In addition, they have characterized their 3D models and and obtained characterized long-term 3D models of TNBC. These models provide unique vehicles for further in-depth investigations to optimize the combination of radiation and CPI therapy, tailoring the treatment to specific characteristics of each tumor.

What's next

In the coming year, Drs. Demaria and Formenti will continue to examine how the molecular subtype of breast cancer affects the ability of radiation therapy to induce the immune signals required for an anti-tumor response. Ongoing studies will continue to examine the genes identified in the last year.  They will also leverage the information derived from their model systems to perform pre-clinical studies to determine ways to monitor an immunogenic response to tumor irradiation.

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Learn more about Susan M. Domchek at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Susan M. Domchek | Researcher | Breast Cancer Research Foundation

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Learn more about Susan M. Domchek at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Basser Professor in Oncology
Executive Director of the Basser Center for BRCA
Director, MacDonald Cancer Risk Evaluation Center
Abramson Family Cancer Center, Perelman School of Medicine

Member, BCRF Scientific Advisory Board

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Susan M. Domchek, MD is the Basser Professor in Oncology at the Perelman School of Medicine of the University of Pennsylvania. She serves as Executive Director of the Basser Center for BRCA at the Abramson Cancer Center and Director of the Mariann and Robert MacDonald Cancer Risk Evaluation Program.
Her work focuses on the genetic evaluation and medical management of individuals with inherited risk factors for cancer. Dr. Domchek is particularly interested in developing new cancer therapies, such as PARP inhibitors, for breast cancer due to genetic risk factors.

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Susan M. Domchek, MD is the Basser Professor in Oncology at the Perelman School of Medicine of the University of Pennsylvania. She serves as Executive Director of the Basser Center for BRCA at the Abramson Cancer Center and Director of the Mariann and Robert MacDonald Cancer Risk Evaluation Program.

Her work focuses on the genetic evaluation and medical management of individuals with inherited risk factors for cancer. Dr. Domchek is particularly interested in developing new cancer therapies, such as PARP inhibitors, for breast cancer due to genetic risk factors.

An elected member of the National Academy of Medicine, the American Society of Clinical Investigation, and the Association of American Physicians, Dr. Domchek is also a member of the American Society of Clinical Oncology for which she had served on a number of committees. A significant contributor to the oncology literature, she has authored/co-authored more than 350 articles appearing in scholarly journals including the New England Journal of Medicine, the Journal of the American Medical Association and the Journal of Clinical Oncology. Dr. Domchek also serves on a number of editorial review boards, including the Journal of Clinical Oncology, as well as on the Scientific Advisory Board for the Breast Cancer Research Foundation.

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Susan M. Domchek, MD is the Basser Professor in Oncology at the Perelman School of Medicine of the University of Pennsylvania. She serves as Executive Director of the Basser Center for BRCA at the Abramson Cancer Center and Director of the Mariann and Robert MacDonald Cancer Risk Evaluation Program.

Her work focuses on the genetic evaluation and medical management of individuals with inherited risk factors for cancer. Dr. Domchek is particularly interested in developing new cancer therapies, such as PARP inhibitors, for breast cancer due to genetic risk factors.

An elected member of the National Academy of Medicine, the American Society of Clinical Investigation, and the Association of American Physicians, Dr. Domchek is also a member of the American Society of Clinical Oncology for which she had served on a number of committees. A significant contributor to the oncology literature, she has authored/co-authored more than 350 articles appearing in scholarly journals including the New England Journal of Medicine, the Journal of the American Medical Association and the Journal of Clinical Oncology. Dr. Domchek also serves on a number of editorial review boards, including the Journal of Clinical Oncology, as well as on the Scientific Advisory Board for the Breast Cancer Research Foundation.

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Research Area: Decreasing barriers to genetic testing and counseling among those at heightened risk of breast and other cancers.

Impact: Men and women with a BRCA gene mutation have an increased risk of developing cancers including ovarian, breast, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek launched the “Point of Care” (POC) Study to test patients with metastatic cancers, to identify those at higher risk for breast, ovarian, prostate, and pancreatic cancer. Identifying cancer-causing gene mutations in patients with and without cancer can have immediate significant impact on the patient and their families, with respect to prevention, early detection, and treatment. The initial results of these studies demonstrated that the delivery models are effective in decreasing barriers to testing and increasing the impact of genetic testing for cancer susceptibility. Dr. Domchek hopes to develop these models to meet real-world demands and allow more individuals to gain timely access to their valuable genetic risk information while remaining embedded in medical care.

Progress Thus Far: To date, the POC study has facilitated the genetic testing of 861 patients—this constitutes more than a 6-fold increase in testing at the University of Pennsylvania Basser Center for BRCA. In other studies, Dr. Domchek’s genetics team (part of an interdisciplinary group at the University of Pennsylvania) is developing a genetic testing component within the electronic medical record (EMR) system to organize genetic information and ease viewability and access. Since its implementation, 9,223 genetic test results have been included making it much easier to find genetic test results in the EMR (or confirm whether genetic testing ever took place).

What’s next: Dr. Domchek and her colleagues will continue their efforts to increase genetic testing so that high-risk individuals can receive increased cancer screening, preventative medication, and potentially prophylactic surgeries. In addition, her team will capitalize on their results and expand their study on EMR-based approaches to enhance and update genetic testing in those with a personal and family history of ovarian cancer.

# data[].attributes.field_current_research.processed
Research Area: Decreasing barriers to genetic testing and counseling among those at heightened risk of breast and other cancers.

Impact: Men and women with a BRCA gene mutation have an increased risk of developing cancers including ovarian, breast, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek launched the “Point of Care” (POC) Study to test patients with metastatic cancers, to identify those at higher risk for breast, ovarian, prostate, and pancreatic cancer. Identifying cancer-causing gene mutations in patients with and without cancer can have immediate significant impact on the patient and their families, with respect to prevention, early detection, and treatment. The initial results of these studies demonstrated that the delivery models are effective in decreasing barriers to testing and increasing the impact of genetic testing for cancer susceptibility. Dr. Domchek hopes to develop these models to meet real-world demands and allow more individuals to gain timely access to their valuable genetic risk information while remaining embedded in medical care.

Progress Thus Far: To date, the POC study has facilitated the genetic testing of 861 patients—this constitutes more than a 6-fold increase in testing at the University of Pennsylvania Basser Center for BRCA. In other studies, Dr. Domchek’s genetics team (part of an interdisciplinary group at the University of Pennsylvania) is developing a genetic testing component within the electronic medical record (EMR) system to organize genetic information and ease viewability and access. Since its implementation, 9,223 genetic test results have been included making it much easier to find genetic test results in the EMR (or confirm whether genetic testing ever took place).

What’s next: Dr. Domchek and her colleagues will continue their efforts to increase genetic testing so that high-risk individuals can receive increased cancer screening, preventative medication, and potentially prophylactic surgeries. In addition, her team will capitalize on their results and expand their study on EMR-based approaches to enhance and update genetic testing in those with a personal and family history of ovarian cancer.

# data[].attributes.field_full_research_summary.value
Research area: Decreasing barriers to genetic testing and counseling among those at heightened risk of breast cancer and other cancers.

Impact: Men and women with a BRCA gene mutation have an increased risk of developing cancers including breast, ovarian, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek is testing genetic screening programs in high-risk groups that could improve testing rates and provide information about how the health care system can better use genetic information to optimize and personalize medical care.

Current investigation: Dr. Domchek and her colleagues will conduct automated searches in electronic medical record (EMR) to identify those at increased risk for inherited genetic predisposition to cancer and will compare two methods of outreach and referral to genetic testing.

What she’s accomplished so far: Dr. Domchek and her collaborators have launched two intervention studies aimed at helping providers and high-risk patients access genetic information and testing. One of her projects, the BRCA Founder Outreach (BFOR) Study, is testing a digital health platform among those of Ashkenazi Jewish ancestry, who have a 1 in 40 chance of having a BRCA mutation—much greater compared the general population. The second, the Point of Care (POC) study, is testing those with metastatic prostate cancer or pancreatic cancer, who sometimes carry BRCA mutations. Identifying those patients with BRCA mutations could have an important impact on family members, who may also have BRCA mutations but do not realize it. These initiatives provide significant advantages for patients by simplifying access to genetic information that can lead to identification of cancer-causing gene mutations in those with and without cancer.

What’s next: Dr. Domchek is expanding her work on decreasing barriers and increasing access to genetic testing. One method involves direct contact with patients through the EMR patient portal. The second method utilizes automated "nudges" to physicians in the EMR. To assess these methods, they will engage primary care colleagues, optimize the use of the EMR, and determine best motivator for patient testing (direct patient contact vs physician nudges), with the ultimate goal of reducing barriers and increasing access to genetic testing to those at greatest risk, while maintaining the testing within a medical model framework. Once feasibility is determined, they will further expand their studies and initiate a large, randomized study across institutions, expanding eligibility criteria and using additional platforms for testing.

# data[].attributes.field_full_research_summary.processed
Research area: Decreasing barriers to genetic testing and counseling among those at heightened risk of breast cancer and other cancers.

Impact: Men and women with a BRCA gene mutation have an increased risk of developing cancers including breast, ovarian, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek is testing genetic screening programs in high-risk groups that could improve testing rates and provide information about how the health care system can better use genetic information to optimize and personalize medical care.

Current investigation: Dr. Domchek and her colleagues will conduct automated searches in electronic medical record (EMR) to identify those at increased risk for inherited genetic predisposition to cancer and will compare two methods of outreach and referral to genetic testing.

What she’s accomplished so far: Dr. Domchek and her collaborators have launched two intervention studies aimed at helping providers and high-risk patients access genetic information and testing. One of her projects, the BRCA Founder Outreach (BFOR) Study, is testing a digital health platform among those of Ashkenazi Jewish ancestry, who have a 1 in 40 chance of having a BRCA mutation—much greater compared the general population. The second, the Point of Care (POC) study, is testing those with metastatic prostate cancer or pancreatic cancer, who sometimes carry BRCA mutations. Identifying those patients with BRCA mutations could have an important impact on family members, who may also have BRCA mutations but do not realize it. These initiatives provide significant advantages for patients by simplifying access to genetic information that can lead to identification of cancer-causing gene mutations in those with and without cancer.

What’s next: Dr. Domchek is expanding her work on decreasing barriers and increasing access to genetic testing. One method involves direct contact with patients through the EMR patient portal. The second method utilizes automated "nudges" to physicians in the EMR. To assess these methods, they will engage primary care colleagues, optimize the use of the EMR, and determine best motivator for patient testing (direct patient contact vs physician nudges), with the ultimate goal of reducing barriers and increasing access to genetic testing to those at greatest risk, while maintaining the testing within a medical model framework. Once feasibility is determined, they will further expand their studies and initiate a large, randomized study across institutions, expanding eligibility criteria and using additional platforms for testing.

# data[].attributes.field_job_title
Basser Professor in Oncology
Executive Director of the Basser Center for BRCA
Director, MacDonald Cancer Risk Evaluation Center
Abramson Family Cancer Center, Perelman School of Medicine

Member, BCRF Scientific Advisory Board

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Decreasing barriers to genetic testing and counseling among those at heightened risk of breast and other cancers.

Impact

Men and women with a BRCA gene mutation have an increased risk of developing cancers including ovarian, breast, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek and several BCRF collaborators have tested delivery models to decrease the barriers to genetic testing in two large studies: the BRCA1/2 Founder Outreach (BFOR) Study that focuses on testing individuals of Ashkenazi ancestry, who have an increased risk of carrying a mutation that is approximately 10 times higher than the general population; and the “Point of Care” (POC) Study to test patients with metastatic cancers, to identify those at higher risk for breast, ovarian, prostate, and pancreatic cancer. Identifying cancer-causing gene mutations in patients with and without cancer can have immediate and significant impact on the patient and their families, with respect to prevention, early detection, and treatment.  These studies demonstrated that the delivery models are effective in decreasing barriers to testing and increasing the impact of genetic testing for cancer susceptibility. Dr. Domchek is adjusting the parameters of these testing models to meet real-world demands and allow more individuals to gain timely access to their valuable genetic risk information while remaining embedded in medical care.

Progress Thus Far

To date, the POC study has facilitated the genetic testing of 861 patients—this constitutes more than a 6-fold increase in testing at Dr. Domchek’s institution. In related work, Dr. Domchek’s genetics team (part of an interdisciplinary group at the University of Pennsylvania) has developed a genetic testing core within the electronic medical record (EMR) system called Precision Medicine Tab (PMT). This EMR enhancement integrates genetic test orders with commercial genetic testing companies to organize genetic information and help clinicians clearly identify those that need testing as well as their test results.  Since its implementation, 9,223 genetic test results have been migrated over to the PMT making it much easier to find genetic test results in the EMR (or confirm whether genetic testing ever took place).

What’s next

Dr. Domchek and her colleagues will continue their efforts to increase genetic testing so that, when needed, individuals can receive increased cancer screening, preventative medication, and potentially prophylactic surgeries. In the coming year, her team will fine-tune efforts toward provider education for primary care physicians so that patients at increased risk for familial cancers can be better identified. In addition, they will expand and further develop EMR reporting and identification tools. The results will enhance and update genetic testing for those with a personal and family history of breast and other cancers.

# data[].attributes.field_research.processed
Decreasing barriers to genetic testing and counseling among those at heightened risk of breast and other cancers.

Impact

Men and women with a BRCA gene mutation have an increased risk of developing cancers including ovarian, breast, prostate, and pancreatic cancer. Genetic testing for BRCA1 and BRCA2 mutations has served as a model for how to use inherited genetic information to guide clinical care. The presence of a BRCA mutation allows doctors to estimate cancer risks, develop a screening and prevention plan, and use targeted therapies for cancers that develop. Despite this, many individuals who carry BRCA mutations have not undergone genetic testing. Dr. Domchek and several BCRF collaborators have tested delivery models to decrease the barriers to genetic testing in two large studies: the BRCA1/2 Founder Outreach (BFOR) Study that focuses on testing individuals of Ashkenazi ancestry, who have an increased risk of carrying a mutation that is approximately 10 times higher than the general population; and the “Point of Care” (POC) Study to test patients with metastatic cancers, to identify those at higher risk for breast, ovarian, prostate, and pancreatic cancer. Identifying cancer-causing gene mutations in patients with and without cancer can have immediate and significant impact on the patient and their families, with respect to prevention, early detection, and treatment.  These studies demonstrated that the delivery models are effective in decreasing barriers to testing and increasing the impact of genetic testing for cancer susceptibility. Dr. Domchek is adjusting the parameters of these testing models to meet real-world demands and allow more individuals to gain timely access to their valuable genetic risk information while remaining embedded in medical care.

Progress Thus Far

To date, the POC study has facilitated the genetic testing of 861 patients—this constitutes more than a 6-fold increase in testing at Dr. Domchek’s institution. In related work, Dr. Domchek’s genetics team (part of an interdisciplinary group at the University of Pennsylvania) has developed a genetic testing core within the electronic medical record (EMR) system called Precision Medicine Tab (PMT). This EMR enhancement integrates genetic test orders with commercial genetic testing companies to organize genetic information and help clinicians clearly identify those that need testing as well as their test results.  Since its implementation, 9,223 genetic test results have been migrated over to the PMT making it much easier to find genetic test results in the EMR (or confirm whether genetic testing ever took place).

What’s next

Dr. Domchek and her colleagues will continue their efforts to increase genetic testing so that, when needed, individuals can receive increased cancer screening, preventative medication, and potentially prophylactic surgeries. In the coming year, her team will fine-tune efforts toward provider education for primary care physicians so that patients at increased risk for familial cancers can be better identified. In addition, they will expand and further develop EMR reporting and identification tools. The results will enhance and update genetic testing for those with a personal and family history of breast and other cancers.

# data[].attributes.metatag_normalized[].attributes.content
Learn more about H. Shelton Earp at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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H. Shelton Earp | Researcher | Breast Cancer Research Foundation

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Learn more about H. Shelton Earp at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

# data[].attributes.metatag_normalized[].attributes.content
Lineberger Professor of Cancer Research
Director, UNC Cancer Care
Professor of Medicine & Pharmacology

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H. Shelton Earp, MD is the Lineberger Professor of Cancer Research, Director of UNC Cancer Care and Director of the UNC Lineberger Comprehensive Cancer. In these roles, he has helped develop basic, clinical and public health research and cancer care at one of the country’s premier public universities and academic medical centers. He serves as Principal Investigator of the UNC Breast Cancer SPORE and his laboratory conducts fundamental and translational research in breast cancer and childhood leukemia. His group has discovered and studied genes involved in a range of cancers, published over 200 biomedical-research articles and been continuously funded by NIH for over 40 years. He is currently collaborating with the UNC Chemical Biology Center in the Eshelman School of Pharmacy to develop a new, first-in-class drug targeting one of the cancer genes discovered in his lab. Inhibition of this gene may stimulate a breast cancer patient’s innate immunity against their cancer.

Dr. Earp has received UNC School of Medicine teaching awards and chaired national review committees for the American Cancer Society and the National Cancer Institute.  He has served as President of the American Association of Cancer Institutes, on the NCI Board of Scientific Advisors, and on the advisory boards of ten university cancer centers.  His lab is supported by NIH grants, the Breast SPORE and the Breast Cancer Research Foundation.

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H. Shelton Earp, MD is the Lineberger Professor of Cancer Research, Director of UNC Cancer Care and Director of the UNC Lineberger Comprehensive Cancer. In these roles, he has helped develop basic, clinical and public health research and cancer care at one of the country’s premier public universities and academic medical centers. He serves as Principal Investigator of the UNC Breast Cancer SPORE and his laboratory conducts fundamental and translational research in breast cancer and childhood leukemia. His group has discovered and studied genes involved in a range of cancers, published over 200 biomedical-research articles and been continuously funded by NIH for over 40 years. He is currently collaborating with the UNC Chemical Biology Center in the Eshelman School of Pharmacy to develop a new, first-in-class drug targeting one of the cancer genes discovered in his lab. Inhibition of this gene may stimulate a breast cancer patient’s innate immunity against their cancer.

Dr. Earp has received UNC School of Medicine teaching awards and chaired national review committees for the American Cancer Society and the National Cancer Institute.  He has served as President of the American Association of Cancer Institutes, on the NCI Board of Scientific Advisors, and on the advisory boards of ten university cancer centers.  His lab is supported by NIH grants, the Breast SPORE and the Breast Cancer Research Foundation.

# data[].attributes.field_current_research.value
Research Area: Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.

Impact: Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp's team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents.  His team is identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Progress Thus Far: Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response.

What’s next: Dr. Earp and his colleagues will continue to build on their previous discoveries by:

continuing to test the action of the small molecule MerTK inhibitors they have developed,

testing the efficacy of these inhibitors in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these small molecule drugs can indeed improve immunotherapy,

utilizing both genetic and pharmacologic experiments to uncover the mechanisms by which MerTK and Tyro3 stimulate immune suppression in TNBC tumors.

Through these studies, they hope to uncover additional genes, like MerTK and Tyro3, that regulate both breast cancer growth and the body's anti-tumor immune response so that more patients may benefit from immunotherapy.

# data[].attributes.field_current_research.processed
Research Area: Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.

Impact: Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp's team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents.  His team is identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Progress Thus Far: Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response.

What’s next: Dr. Earp and his colleagues will continue to build on their previous discoveries by:

continuing to test the action of the small molecule MerTK inhibitors they have developed,

testing the efficacy of these inhibitors in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these small molecule drugs can indeed improve immunotherapy,

utilizing both genetic and pharmacologic experiments to uncover the mechanisms by which MerTK and Tyro3 stimulate immune suppression in TNBC tumors.

Through these studies, they hope to uncover additional genes, like MerTK and Tyro3, that regulate both breast cancer growth and the body's anti-tumor immune response so that more patients may benefit from immunotherapy.

# data[].attributes.field_full_research_summary.value
Research goal: Identifying genes that regulate breast cancer growth and the body’s immune response to breast cancer which may be targeted to improve the efficacy of immunotherapy.

Impact: Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. His team discovered the MerTK gene which plays a complex role in breast cancer cell survival and metastasis. They showed that MerTK sends immunosuppressive signals that prevent adequate immune responses from patients which results in resistance to immunotherapy. He and his team are identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Current investigation: Characterizing the MerTK gene and determining whether inhibiting MerTK or genes like it could create a strong, anti-tumor immune response and improve the effectiveness of immunotherapy.

What he’s learned so far: In previous studies, Dr. Earp’s team has shown that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. Moreover, they have discovered the MerTK gene which blocks the effect of immunotherapeutic agents and leads to therapy resistance. Conversely, they showed that deleting MerTK enhances the immune response, slows tumor growth and decreases metastasis. He and his team have also found that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response.

What’s next: Dr. Earp’s team will use both genetic and pharmacologic experiments to uncover the mechanisms by which MerTK and Tyro3 stimulate immune suppression in breast cancer, specifically TNBC. In addition, they will determine whether inhibition of these signaling molecules can make other forms of breast cancer therapy more effective. They hope to uncover additional genes like MerTK and Tyro3 that regulate both breast cancer growth and the body’s immune response to breast cancer so that more patients may benefit from immunotherapy.

# data[].attributes.field_full_research_summary.processed
Research goal: Identifying genes that regulate breast cancer growth and the body’s immune response to breast cancer which may be targeted to improve the efficacy of immunotherapy.

Impact: Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. His team discovered the MerTK gene which plays a complex role in breast cancer cell survival and metastasis. They showed that MerTK sends immunosuppressive signals that prevent adequate immune responses from patients which results in resistance to immunotherapy. He and his team are identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Current investigation: Characterizing the MerTK gene and determining whether inhibiting MerTK or genes like it could create a strong, anti-tumor immune response and improve the effectiveness of immunotherapy.

What he’s learned so far: In previous studies, Dr. Earp’s team has shown that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. Moreover, they have discovered the MerTK gene which blocks the effect of immunotherapeutic agents and leads to therapy resistance. Conversely, they showed that deleting MerTK enhances the immune response, slows tumor growth and decreases metastasis. He and his team have also found that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response.

What’s next: Dr. Earp’s team will use both genetic and pharmacologic experiments to uncover the mechanisms by which MerTK and Tyro3 stimulate immune suppression in breast cancer, specifically TNBC. In addition, they will determine whether inhibition of these signaling molecules can make other forms of breast cancer therapy more effective. They hope to uncover additional genes like MerTK and Tyro3 that regulate both breast cancer growth and the body’s immune response to breast cancer so that more patients may benefit from immunotherapy.

# data[].attributes.field_job_title
Lineberger Professor of Cancer Research
Director, UNC Cancer Care
Professor of Medicine & Pharmacology

# data[].attributes.field_research.value
Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.

Impact

Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp's team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents.  His team is identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Progress Thus Far

Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response. To determine how MerTk and Tyro3 exert their influence, Dr. Earp and his collaborators developed laboratory models that recapitulate triple-negative breast cancer. In the last year, these models allowed his team to demonstrate that decreasing MerTK or Tyro3 dramatically increases the ability of immune cells to attack tumors.

What’s next

The team will continue to build on their previous discoveries and assess the mechanism by which the absence of MerTK or Tyro3 mediates immune function against tumor cells. They will employ several techniques to examine the RNA expression in various immune cells of the tumor microenvironment and assess the spatial relationship between these immune cells and breast tumor cells. They will also continue to test previously developed small molecule MerTk inhibitors alone and in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these small molecule drugs can indeed improve immunotherapy. The results of these studies have the potential to unveil new ways to improve the efficacy of T-cell directed therapies so that more patients may benefit from immunotherapy, particularly TNBC patients that have few therapeutic options.

# data[].attributes.field_research.processed
Improving the efficacy of immunotherapy by identifying target genes that regulate breast cancer growth and the immune response to breast cancer.

Impact

Immunotherapy has recently been used in the treatment of breast cancer with only modest benefit. Dr. Earp is examining the factors in the microenvironment of breast tumors that may be involved in suppressing a robust immune response in patients undergoing immunotherapy. Dr. Earp's team demonstrated that breast cancers evolve to recruit immunosuppressive cells into the tumor bed. This led to the discovery of the MerTK gene which plays a complex role in breast cancer cell survival and metastasis by blocking the effect of immunotherapy agents.  His team is identifying novel strategies that could reverse the effects of MerTK and enhance the effectiveness of immunotherapy.

Progress Thus Far

Dr. Earp and his colleagues showed that deleting MerTK enhances the immune response, slows tumor growth, and decreases metastasis in laboratory models. His team has developed a series of small molecule inhibitors of MerTK and shown that, in combination with chemotherapy, they can block tumor survival. Other studies have revealed that circulating immune cells in the blood of patients with metastatic triple-negative breast cancer (TNBC) have higher levels of MerTK than immune cells from healthy patients. His team has also identified an additional signaling molecule, Tyro3, that suppresses the immune response. To determine how MerTk and Tyro3 exert their influence, Dr. Earp and his collaborators developed laboratory models that recapitulate triple-negative breast cancer. In the last year, these models allowed his team to demonstrate that decreasing MerTK or Tyro3 dramatically increases the ability of immune cells to attack tumors.

What’s next

The team will continue to build on their previous discoveries and assess the mechanism by which the absence of MerTK or Tyro3 mediates immune function against tumor cells. They will employ several techniques to examine the RNA expression in various immune cells of the tumor microenvironment and assess the spatial relationship between these immune cells and breast tumor cells. They will also continue to test previously developed small molecule MerTk inhibitors alone and in combination with immunotherapy (anti-PD1 or anti-PD-L1) to confirm that these small molecule drugs can indeed improve immunotherapy. The results of these studies have the potential to unveil new ways to improve the efficacy of T-cell directed therapies so that more patients may benefit from immunotherapy, particularly TNBC patients that have few therapeutic options.

# data[].attributes.metatag_normalized[].attributes.content
Learn more about Stanislav Emelianov at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Stanislav Emelianov | Researcher | Breast Cancer Research Foundation

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Learn more about Stanislav Emelianov at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Joseph M. Pettit Endowed Chair
Georgia Research Alliance Eminent Scholar
Professor of Electrical & Computer Engineering and Biomedical Engineering
Georgia Institute of Technology and Emory School of Medicine
Atlanta, Georgia

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Dr. Stanislav Emelianov is a Joseph M. Pettit Endowed Chair, Georgia Research Alliance Eminent Scholar, and Professor of Biomedical Engineering and Electrical & Computer Engineering at the Georgia Institute of Technology. He is also appointed at Emory University School of Medicine where he is affiliated with Winship Cancer Institute, Department of Radiology, and other clinical units. Furthermore, Dr.

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Dr. Stanislav Emelianov is a Joseph M. Pettit Endowed Chair, Georgia Research Alliance Eminent Scholar, and Professor of Biomedical Engineering and Electrical & Computer Engineering at the Georgia Institute of Technology. He is also appointed at Emory University School of Medicine where he is affiliated with Winship Cancer Institute, Department of Radiology, and other clinical units. Furthermore, Dr. Emelianov is Director of the Ultrasound Imaging and Therapeutics Research Laboratory at the Georgia Institute of Technology focused on the translation of diagnostic imaging & therapeutic instrumentation, and nanobiotechnology for clinical applications.

Dr. Emelianov’s career has been devoted to the development of advanced imaging methods, assisting treatment planning, and enhancing image-guided therapy and monitoring of the treatment outcome. He is specifically interested in intelligent biomedical imaging and sensing and has developed approaches for image-guided molecular therapy and therapeutic applications of ultrasound and electromagnetic energy. Dr Emelianov has pioneered several ultrasound-based imaging techniques including shear wave elasticity imaging and molecular photoacoustic imaging. Projects in Dr. Emelianov's laboratory, which focuses on cancer and other diseases, range from molecular imaging to functional imaging and tissue differentiation, from drug delivery and release to image-guided surgery and intervention.

Dr. Emelianov is a nationally recognized expert in biomedical imaging instrumentation and nanoagents for imaging and therapy. He is the author of over 500 publications including peer-reviewed research articles, invited reviews, book chapters, and conference proceedings. In recognition of his contributions to the field, Dr. Emelianov was elected to the College of Fellows of the American Institute for Medical and Biological Engineering. He is past Vice-President for Ultrasonics of the IEEE Ultrasonics, Ferroelectrics and Frequency Control Society, and senior member of several professional organizations.

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Dr. Stanislav Emelianov is a Joseph M. Pettit Endowed Chair, Georgia Research Alliance Eminent Scholar, and Professor of Biomedical Engineering and Electrical & Computer Engineering at the Georgia Institute of Technology. He is also appointed at Emory University School of Medicine where he is affiliated with Winship Cancer Institute, Department of Radiology, and other clinical units. Furthermore, Dr. Emelianov is Director of the Ultrasound Imaging and Therapeutics Research Laboratory at the Georgia Institute of Technology focused on the translation of diagnostic imaging & therapeutic instrumentation, and nanobiotechnology for clinical applications.

Dr. Emelianov’s career has been devoted to the development of advanced imaging methods, assisting treatment planning, and enhancing image-guided therapy and monitoring of the treatment outcome. He is specifically interested in intelligent biomedical imaging and sensing and has developed approaches for image-guided molecular therapy and therapeutic applications of ultrasound and electromagnetic energy. Dr Emelianov has pioneered several ultrasound-based imaging techniques including shear wave elasticity imaging and molecular photoacoustic imaging. Projects in Dr. Emelianov's laboratory, which focuses on cancer and other diseases, range from molecular imaging to functional imaging and tissue differentiation, from drug delivery and release to image-guided surgery and intervention.

Dr. Emelianov is a nationally recognized expert in biomedical imaging instrumentation and nanoagents for imaging and therapy. He is the author of over 500 publications including peer-reviewed research articles, invited reviews, book chapters, and conference proceedings. In recognition of his contributions to the field, Dr. Emelianov was elected to the College of Fellows of the American Institute for Medical and Biological Engineering. He is past Vice-President for Ultrasonics of the IEEE Ultrasonics, Ferroelectrics and Frequency Control Society, and senior member of several professional organizations.

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Goal: To develop novel strategies for breast cancer imaging and image-guided therapy.

Impact: Dr. Emelianov and his team have created new medical imaging devices and agents to detect, differentiate, treat, and monitor breast cancer and lymph node metastases. Such technology will help provide a comprehensive approach to the clinical management of breast cancer.

What’s next: The team will continue to focus on the development and clinical translation of an advanced imaging technology that combines complementary imaging techniques to visualize regional lymph nodes of breast cancer patients. Dr. Emelianov is also developing nanoparticles to aid in imaging and therapeutic delivery.

When patients undergo breast cancer therapy, imaging is used to determine whether the cancer has spread to other tissues so that treatment plans can be adjusted to prevent metastasis. Dr. Emelianov is studying advanced imaging methods that provide highly detailed information about cancer cells, which will help him develop an imaging platform capable of non-invasive and safe diagnostic imaging and image-guided therapy of breast cancer, a technology called theranostics.

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Goal: To develop novel strategies for breast cancer imaging and image-guided therapy.

Impact: Dr. Emelianov and his team have created new medical imaging devices and agents to detect, differentiate, treat, and monitor breast cancer and lymph node metastases. Such technology will help provide a comprehensive approach to the clinical management of breast cancer.

What’s next: The team will continue to focus on the development and clinical translation of an advanced imaging technology that combines complementary imaging techniques to visualize regional lymph nodes of breast cancer patients. Dr. Emelianov is also developing nanoparticles to aid in imaging and therapeutic delivery.

When patients undergo breast cancer therapy, imaging is used to determine whether the cancer has spread to other tissues so that treatment plans can be adjusted to prevent metastasis. Dr. Emelianov is studying advanced imaging methods that provide highly detailed information about cancer cells, which will help him develop an imaging platform capable of non-invasive and safe diagnostic imaging and image-guided therapy of breast cancer, a technology called theranostics.

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Research area: To augment emerging imaging technologies with molecularly targeted nano-sized agents to aid in breast cancer diagnostic imaging and image-guided therapy.

Impact: Dr. Emelianov’s imaging technology will provide patient-specific information and, therefore, play a critical role in more accurate detection and characterization of breast cancer and lymph node micrometastases. Other benefits include superior targeting and guidance of tissue biopsy, image-guided interventions and non-invasive therapy, and longitudinal monitoring of breast cancer treatment outcome.

Current investigation: The team is focused on advancing clinical evaluation of the presence of regional lymph node metastases in breast cancer through emerging ultrasound imaging technologies. Determination of whether a malignancy has spread through regional lymph nodes in patients is an important factor used to develop a therapeutic plan and to predict prognosis.

What he’s accomplished so far: With BCRF support, Dr. Emelianov’s team has created a new medical imaging and theranostic platform to detect, differentiate, treat, and monitor breast cancer and lymph node metastases and have demonstrated the utility of their system in image-guided treatment of lymph node metastases in breast cancer patients.

What’s next: Dr. Emelianov will explore the clinical utility of non-invasive, label-free imaging of regional lymph nodes of breast cancer patients. He and his team are developing and testing theranostic nanodroplets that aid in imaging and deliver a therapeutic agent. Dr. Emelianov is also developing new technologies that will enable imaging of the continuously changing tumor microenvironment that surrounds and interacts with tumor cells.

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Research area: To augment emerging imaging technologies with molecularly targeted nano-sized agents to aid in breast cancer diagnostic imaging and image-guided therapy.

Impact: Dr. Emelianov’s imaging technology will provide patient-specific information and, therefore, play a critical role in more accurate detection and characterization of breast cancer and lymph node micrometastases. Other benefits include superior targeting and guidance of tissue biopsy, image-guided interventions and non-invasive therapy, and longitudinal monitoring of breast cancer treatment outcome.

Current investigation: The team is focused on advancing clinical evaluation of the presence of regional lymph node metastases in breast cancer through emerging ultrasound imaging technologies. Determination of whether a malignancy has spread through regional lymph nodes in patients is an important factor used to develop a therapeutic plan and to predict prognosis.

What he’s accomplished so far: With BCRF support, Dr. Emelianov’s team has created a new medical imaging and theranostic platform to detect, differentiate, treat, and monitor breast cancer and lymph node metastases and have demonstrated the utility of their system in image-guided treatment of lymph node metastases in breast cancer patients.

What’s next: Dr. Emelianov will explore the clinical utility of non-invasive, label-free imaging of regional lymph nodes of breast cancer patients. He and his team are developing and testing theranostic nanodroplets that aid in imaging and deliver a therapeutic agent. Dr. Emelianov is also developing new technologies that will enable imaging of the continuously changing tumor microenvironment that surrounds and interacts with tumor cells.

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Joseph M. Pettit Endowed Chair
Georgia Research Alliance Eminent Scholar
Professor of Electrical & Computer Engineering and Biomedical Engineering
Georgia Institute of Technology and Emory School of Medicine
Atlanta, Georgia

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Improving immunotherapy in breast cancer.

Impact

Immunotherapies are revolutionizing oncology by providing a new method to target tumors: they activate the immune system to recognize and attack cancer. One type of immunotherapy, known as cellular immunotherapy, cultivates a patient’s own immune cells, manipulates them in the laboratory so that they become cancer-killing machines, and reintroduces them to the patient. They are highly effective in blood cancers but not in most “solid” cancers like breast cancer. The primary challenge is that cellular immunotherapies largely fail to infilitrate and remain inside the tumor, which prevents them from working effectively. In addition, real-time tracking of the cells once they are inside patients is not feasible, which makes it difficult to understand how they are functioning and how we can continue to improve their use as therapies. Dr. Emelianov and his team are generating a new approach that will allow for direct delivery of cellular immunotherapies to the tumors, and enable monitoring of the cells’ location through imaging.

What’s next

The team aims to engineer T cells (a type of immune cell) with photomagnetic nanoparticles. Thus far, they successfully attached these nanoparticles to the surface of T cells without interfering with the cells’ ability to function. The nanoparticles are engineered to be visible through medical imaging, such ultrasound and MRI, and magnetic which means they can be guided to a target site—like tumors—by applying an external magnetic field to the tissue. This essentially would force cellular immunotherapies to home to tumors, with the aim of improving their accumulation, retention, and therapeutic outcomes. In the current funding year, Dr. Emelianov and his team will test their technolology and assess imaging biomarkers (like tumor volume, blood flow and oxygenation, tissue stiffness, etc.) to provide feedback on therapeutic outcomes and identify treatment responders.

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Improving immunotherapy in breast cancer.

Impact

Immunotherapies are revolutionizing oncology by providing a new method to target tumors: they activate the immune system to recognize and attack cancer. One type of immunotherapy, known as cellular immunotherapy, cultivates a patient’s own immune cells, manipulates them in the laboratory so that they become cancer-killing machines, and reintroduces them to the patient. They are highly effective in blood cancers but not in most “solid” cancers like breast cancer. The primary challenge is that cellular immunotherapies largely fail to infilitrate and remain inside the tumor, which prevents them from working effectively. In addition, real-time tracking of the cells once they are inside patients is not feasible, which makes it difficult to understand how they are functioning and how we can continue to improve their use as therapies. Dr. Emelianov and his team are generating a new approach that will allow for direct delivery of cellular immunotherapies to the tumors, and enable monitoring of the cells’ location through imaging.

What’s next

The team aims to engineer T cells (a type of immune cell) with photomagnetic nanoparticles. Thus far, they successfully attached these nanoparticles to the surface of T cells without interfering with the cells’ ability to function. The nanoparticles are engineered to be visible through medical imaging, such ultrasound and MRI, and magnetic which means they can be guided to a target site—like tumors—by applying an external magnetic field to the tissue. This essentially would force cellular immunotherapies to home to tumors, with the aim of improving their accumulation, retention, and therapeutic outcomes. In the current funding year, Dr. Emelianov and his team will test their technolology and assess imaging biomarkers (like tumor volume, blood flow and oxygenation, tissue stiffness, etc.) to provide feedback on therapeutic outcomes and identify treatment responders.

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Learn more about Charis Eng at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Charis Eng | Researcher | Breast Cancer Research Foundation

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Learn more about Charis Eng at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Chairwoman, Genomic Medicine Institute, Cleveland Clinic
American Cancer Society Clinical Research Professor
Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine
Professor and Vice Chair, Department of Genetics
Case Western Reserve University
Cleveland, Ohio

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Charis Eng, MD, PhD is the founding Chair of the Genomic Medicine Institute at the Cleveland Clinic, founding Director of the institute’s clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine. She was honored with the Hardis Endowed Chair in Cancer Genomic Medicine in 2008 and the American Cancer Society Clinical Research Professorship in 2009.

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Charis Eng, MD, PhD is the founding Chair of the Genomic Medicine Institute at the Cleveland Clinic, founding Director of the institute’s clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine. She was honored with the Hardis Endowed Chair in Cancer Genomic Medicine in 2008 and the American Cancer Society Clinical Research Professorship in 2009. In 2011, she was elected to the Institute of Medicine of the US National Academies of Sciences for her achievements and leadership in genetics- and genomics-based research and personalized healthcare. Her research has been acknowledged as the paradigm for performing cancer genetics research which can be brought to clinical practice. At the clinical interface, she is acknowledged as one of the rare "go to" people on what is and how to implement genetic- and genomics-enabled personalized healthcare.

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Charis Eng, MD, PhD is the founding Chair of the Genomic Medicine Institute at the Cleveland Clinic, founding Director of the institute’s clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine. She was honored with the Hardis Endowed Chair in Cancer Genomic Medicine in 2008 and the American Cancer Society Clinical Research Professorship in 2009. In 2011, she was elected to the Institute of Medicine of the US National Academies of Sciences for her achievements and leadership in genetics- and genomics-based research and personalized healthcare. Her research has been acknowledged as the paradigm for performing cancer genetics research which can be brought to clinical practice. At the clinical interface, she is acknowledged as one of the rare "go to" people on what is and how to implement genetic- and genomics-enabled personalized healthcare.

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Research Area: Uncovering the complex biology behind inherited cancers to better predict risk and discover new therapeutic strategies for patients.

Impact: Genetics are a major contributor to heritable breast cancer, but not all patients with mutated genes will develop the disease. For those who do develop cancer, scientists remain unsure as to why, and this hampers the design of effective predictive tests, prevention strategies, and therapies. BRCA mutations are the most well-known inherited mutations for breast cancer, but there are many more. Dr. Eng studies the gene PTEN, which her group identified as a tumor suppressor—it prevents healthy cells from becoming cancerous. When PTEN it is altered its tumor-blocking functions can be lost. The importance of PTEN is underscored in the familial cancer disorder PTEN Hamartoma Syndrome (PHTS). These individuals inherit mutations in PTEN and have an 85 percent risk of developing breast cancer and other cancers. Dr. Eng’s work explores what additional factors are required to tip the scales and initiate cancer in individuals with PHTS, which could also inform our understanding of how cancer forms in other heritable breast cancers.

Progress Thus Far: Several biological factors could induce cancer in individuals with PTEN mutations, including additional inherited genetic alterations; spontaneous mutations that develop during a patient’s lifetime; and systemic, non-genetic, changes in the body (e.g., changes in metabolism or immunity). Dr. Eng and team pursued another inherited genetic alteration in the gene WWP2 and found that it is associated with reducing PTEN levels. Dr. Eng’s team also revealed that PHTS-related breast tumors are genetically unique when compared to non-heritable breast cancers, potentially dulling the effectiveness of conventional therapies in this population. The team also looked at the role of metabolism—tumors have their own unique processes for sugar, oxygen, and other nutrients—and found that metabolic processes differ between PHTS individuals with cancer versus those without.

What’s next: Dr. Eng and team will work to confirm if WWP2 is a regulator of PTEN, making it a potential diagnostic factor and therapeutic target for some PHTS patients. And after identifying distinct metabolic profiles between PHTS individuals with and without cancer, Dr. Eng’s team will see if they can generate a “metabotype”—a list of cancer-specific metabolites that could be used in a laboratory test to predict cancer risk for PHTS.

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Research Area: Uncovering the complex biology behind inherited cancers to better predict risk and discover new therapeutic strategies for patients.

Impact: Genetics are a major contributor to heritable breast cancer, but not all patients with mutated genes will develop the disease. For those who do develop cancer, scientists remain unsure as to why, and this hampers the design of effective predictive tests, prevention strategies, and therapies. BRCA mutations are the most well-known inherited mutations for breast cancer, but there are many more. Dr. Eng studies the gene PTEN, which her group identified as a tumor suppressor—it prevents healthy cells from becoming cancerous. When PTEN it is altered its tumor-blocking functions can be lost. The importance of PTEN is underscored in the familial cancer disorder PTEN Hamartoma Syndrome (PHTS). These individuals inherit mutations in PTEN and have an 85 percent risk of developing breast cancer and other cancers. Dr. Eng’s work explores what additional factors are required to tip the scales and initiate cancer in individuals with PHTS, which could also inform our understanding of how cancer forms in other heritable breast cancers.

Progress Thus Far: Several biological factors could induce cancer in individuals with PTEN mutations, including additional inherited genetic alterations; spontaneous mutations that develop during a patient’s lifetime; and systemic, non-genetic, changes in the body (e.g., changes in metabolism or immunity). Dr. Eng and team pursued another inherited genetic alteration in the gene WWP2 and found that it is associated with reducing PTEN levels. Dr. Eng’s team also revealed that PHTS-related breast tumors are genetically unique when compared to non-heritable breast cancers, potentially dulling the effectiveness of conventional therapies in this population. The team also looked at the role of metabolism—tumors have their own unique processes for sugar, oxygen, and other nutrients—and found that metabolic processes differ between PHTS individuals with cancer versus those without.

What’s next: Dr. Eng and team will work to confirm if WWP2 is a regulator of PTEN, making it a potential diagnostic factor and therapeutic target for some PHTS patients. And after identifying distinct metabolic profiles between PHTS individuals with and without cancer, Dr. Eng’s team will see if they can generate a “metabotype”—a list of cancer-specific metabolites that could be used in a laboratory test to predict cancer risk for PHTS.

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Research area: Identifying and characterizing biological factors that are associated with genetic mutations that increase breast cancer risk.

Impact: The PTEN gene has been identified as a tumor suppressor gene which, when mutated or dysregulated, increases the risk of several cancers including breast cancer. PTEN mutations confer an 85 percent lifetime risk of developing breast cancer. Currently, there is no way to predict which PTEN carriers will eventually develop breast cancer. Dr. Eng and her colleagues are focused on determining the factors associated with mutations in the PTEN gene and their role in hereditary breast cancer risk. Their findings may lead to the identification of novel targets for prevention and therapy in this high-risk group.

Current investigation: She and her colleagues are employing a multi-faceted approach to identify and characterize factors associated with PTEN mutations which may accurately predict which carriers of these alterations will develop breast cancer.

What she’s learned so far: Dr. Eng and her team have shown that alterations in energy-associated genes specifically SDHx (succinate dehydrogenase gene) together with PTEN mutations confer a higher risk of breast cancer than mutations in either gene alone. In fact, they have reported that among PTEN mutation carriers, variations in the SDHx gene raise breast cancer risk to almost 100 percent. In the last year, Dr. Eng’s team discovered five candidate susceptibility genes in patients harboring PTEN/SDHx mutations including one gene that regulates PTEN. They have identified WWP2 as one of these candidate genes and will conduct further studies to functionally characterize it.

What’s next: This year, the team will continue to characterize the WWP2 gene and its role in breast cancer risk. They will also study breast cancer-risk modifiers in PTEN mutation carriers and delve deeply into the metabolite imbalances in PTEN-associated breast cancer that may provide biomarkers and potential therapeutic targets.

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Research area: Identifying and characterizing biological factors that are associated with genetic mutations that increase breast cancer risk.

Impact: The PTEN gene has been identified as a tumor suppressor gene which, when mutated or dysregulated, increases the risk of several cancers including breast cancer. PTEN mutations confer an 85 percent lifetime risk of developing breast cancer. Currently, there is no way to predict which PTEN carriers will eventually develop breast cancer. Dr. Eng and her colleagues are focused on determining the factors associated with mutations in the PTEN gene and their role in hereditary breast cancer risk. Their findings may lead to the identification of novel targets for prevention and therapy in this high-risk group.

Current investigation: She and her colleagues are employing a multi-faceted approach to identify and characterize factors associated with PTEN mutations which may accurately predict which carriers of these alterations will develop breast cancer.

What she’s learned so far: Dr. Eng and her team have shown that alterations in energy-associated genes specifically SDHx (succinate dehydrogenase gene) together with PTEN mutations confer a higher risk of breast cancer than mutations in either gene alone. In fact, they have reported that among PTEN mutation carriers, variations in the SDHx gene raise breast cancer risk to almost 100 percent. In the last year, Dr. Eng’s team discovered five candidate susceptibility genes in patients harboring PTEN/SDHx mutations including one gene that regulates PTEN. They have identified WWP2 as one of these candidate genes and will conduct further studies to functionally characterize it.

What’s next: This year, the team will continue to characterize the WWP2 gene and its role in breast cancer risk. They will also study breast cancer-risk modifiers in PTEN mutation carriers and delve deeply into the metabolite imbalances in PTEN-associated breast cancer that may provide biomarkers and potential therapeutic targets.

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Chairwoman, Genomic Medicine Institute, Cleveland Clinic
American Cancer Society Clinical Research Professor
Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine
Professor and Vice Chair, Department of Genetics
Case Western Reserve University
Cleveland, Ohio

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Uncovering the complex biology behind inherited cancers to better predict risk and discover new therapeutic strategies for patients.

Impact

Genetics are a major contributor to heritable breast cancer, but not all patients with mutated genes will develop the disease. For those who do develop cancer, scientists remain unsure as to why, and this hampers the design of effective predictive tests, prevention strategies, and therapies. BRCA mutations are the most well-known inherited mutations for breast cancer, but there are many more. Dr. Eng studies the gene PTEN, which her group identified as a tumor suppressor—it prevents healthy cells from becoming cancerous. When PTEN it is altered its tumor-blocking functions can be lost. The importance of PTEN is underscored in the familial cancer disorder PTEN Hamartoma Syndrome (PHTS). These individuals inherit mutations in PTEN and have an 85 percent risk of developing breast cancer and other cancers. Dr. Eng’s work explores what additional factors are required to tip the scales and initiate cancer in individuals with PHTS, which could also inform our understanding of how cancer forms in other heritable breast cancers.

Progress Thus Far

Several biological factors could induce cancer in individuals with PTEN mutations, including additional inherited genetic alterations; spontaneous mutations that develop during a patient’s lifetime; and systemic, non-genetic, changes in the body (e.g., changes in metabolism or immunity). To further characterize the genetic makeup of PHTS cancers, and identify mutations that may contribute to cancer development, Dr. Eng’s team analyzed the DNA of 600 PHTS patients and their family members. Ultimately, they did find several genetic alterations that are associated with cancer in PHTS, which require further study. In addition, the team assessed breast tissues from PHTS patients to show that their cancers are genetically and molecularly different from non-PHTS breast cancers. The team also continued their study of the role of metabolism—tumors have their own unique processes for sugar, oxygen, and other nutrients—and found cancer-specific metabolites that could serve as biomarkers of cancer risk in PHTS.

What’s next

To characterize the potential genetic and metabolic factors that can contribute to breast cancer risk in PHTS patients, the team will further their studies by assessing each PHTS patient’s unique genetic makeup and exploring if changes in metabolites are affected by a patient’s genetics. They will also assess PHTS’ patients breast cancer genomes to determine their cancers are distinct from those lacking an inherited PTEN mutation. This may result in new therapeutic and preventative drug targets for these patients. Overall, the proposed work is important for transforming our understanding of breast cancer development and prevention on an individual level.

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Uncovering the complex biology behind inherited cancers to better predict risk and discover new therapeutic strategies for patients.

Impact

Genetics are a major contributor to heritable breast cancer, but not all patients with mutated genes will develop the disease. For those who do develop cancer, scientists remain unsure as to why, and this hampers the design of effective predictive tests, prevention strategies, and therapies. BRCA mutations are the most well-known inherited mutations for breast cancer, but there are many more. Dr. Eng studies the gene PTEN, which her group identified as a tumor suppressor—it prevents healthy cells from becoming cancerous. When PTEN it is altered its tumor-blocking functions can be lost. The importance of PTEN is underscored in the familial cancer disorder PTEN Hamartoma Syndrome (PHTS). These individuals inherit mutations in PTEN and have an 85 percent risk of developing breast cancer and other cancers. Dr. Eng’s work explores what additional factors are required to tip the scales and initiate cancer in individuals with PHTS, which could also inform our understanding of how cancer forms in other heritable breast cancers.

Progress Thus Far

Several biological factors could induce cancer in individuals with PTEN mutations, including additional inherited genetic alterations; spontaneous mutations that develop during a patient’s lifetime; and systemic, non-genetic, changes in the body (e.g., changes in metabolism or immunity). To further characterize the genetic makeup of PHTS cancers, and identify mutations that may contribute to cancer development, Dr. Eng’s team analyzed the DNA of 600 PHTS patients and their family members. Ultimately, they did find several genetic alterations that are associated with cancer in PHTS, which require further study. In addition, the team assessed breast tissues from PHTS patients to show that their cancers are genetically and molecularly different from non-PHTS breast cancers. The team also continued their study of the role of metabolism—tumors have their own unique processes for sugar, oxygen, and other nutrients—and found cancer-specific metabolites that could serve as biomarkers of cancer risk in PHTS.

What’s next

To characterize the potential genetic and metabolic factors that can contribute to breast cancer risk in PHTS patients, the team will further their studies by assessing each PHTS patient’s unique genetic makeup and exploring if changes in metabolites are affected by a patient’s genetics. They will also assess PHTS’ patients breast cancer genomes to determine their cancers are distinct from those lacking an inherited PTEN mutation. This may result in new therapeutic and preventative drug targets for these patients. Overall, the proposed work is important for transforming our understanding of breast cancer development and prevention on an individual level.

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Learn more about Laura J. Esserman at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Laura J. Esserman | Researcher | Breast Cancer Research Foundation

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Learn more about Laura J. Esserman at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Director, Carol Franc Buck Breast Care Center
Professor of Surgery and Radiology
Clinical Program Leader, Breast Oncology Program
Alfred A. de Lorimier Endowed Chair in General Surgery
UCSF Helen Diller Family Comprehensive Cancer Center

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Laura Esserman, MD, MBA, an internationally recognized breast surgeon, breast oncology specialist, and visionary in personalized medicine, is revolutionizing breast cancer screening and treatment throughout our nation today. Her breast cancer work spans a spectrum from basic science to public policy issues and the impact of both on the delivery of clinical care. She is a provocative thought leader calling attention to, and finding solutions for, over-diagnosis and over-treatment of breast cancer, especially of DCIS.

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Laura Esserman, MD, MBA, an internationally recognized breast surgeon, breast oncology specialist, and visionary in personalized medicine, is revolutionizing breast cancer screening and treatment throughout our nation today. Her breast cancer work spans a spectrum from basic science to public policy issues and the impact of both on the delivery of clinical care. She is a provocative thought leader calling attention to, and finding solutions for, over-diagnosis and over-treatment of breast cancer, especially of DCIS.

Since 2002, Dr. Esserman has led the I-SPY TRIALS, a ground-breaking national public-private collaboration among NCI, FDA, more than 20 cancer research centers, and major pharma and biotech companies. This trial model, which has now become an international model for translational research, is designed to shave several years and tens of millions of dollars off the drug development process. The trial paradigm is now being developed for use in other disease domains.

Additionally, Dr. Esserman led the creation of the University of California-wide Athena Breast Health Network, a learning system designed to integrate clinical care and research as it follows 150,000 women from screening through treatment and outcomes.  As part of the network, she has spearheaded the development of the WISDOM study to learn how to improve breast cancer screening by testing and comparing the safety and efficacy of a personalized screening strategy informed by each woman’s breast cancer risk and preferences against the standard of annual screening.

Dr. Esserman has published more than 300 articles in peer-reviewed journals, and is regularly consulted by prestigious scientific, business, and consumer media including The New York Times, Wall Street Journal, Los Angeles Times, Health Magazine, Prevention Magazine, The Newshour, ABC World News, the NBC Nightly News, the CBS Evening News, and NPR’s Science Friday.

She was included as one of TIME Magazine’s 100 Most Influential People of 2016, and she also received the 2018 Giant of Cancer Care® in Cancer Diagnostics award.

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Laura Esserman, MD, MBA, an internationally recognized breast surgeon, breast oncology specialist, and visionary in personalized medicine, is revolutionizing breast cancer screening and treatment throughout our nation today. Her breast cancer work spans a spectrum from basic science to public policy issues and the impact of both on the delivery of clinical care. She is a provocative thought leader calling attention to, and finding solutions for, over-diagnosis and over-treatment of breast cancer, especially of DCIS.

Since 2002, Dr. Esserman has led the I-SPY TRIALS, a ground-breaking national public-private collaboration among NCI, FDA, more than 20 cancer research centers, and major pharma and biotech companies. This trial model, which has now become an international model for translational research, is designed to shave several years and tens of millions of dollars off the drug development process. The trial paradigm is now being developed for use in other disease domains.

Additionally, Dr. Esserman led the creation of the University of California-wide Athena Breast Health Network, a learning system designed to integrate clinical care and research as it follows 150,000 women from screening through treatment and outcomes.  As part of the network, she has spearheaded the development of the WISDOM study to learn how to improve breast cancer screening by testing and comparing the safety and efficacy of a personalized screening strategy informed by each woman’s breast cancer risk and preferences against the standard of annual screening.

Dr. Esserman has published more than 300 articles in peer-reviewed journals, and is regularly consulted by prestigious scientific, business, and consumer media including The New York Times, Wall Street Journal, Los Angeles Times, Health Magazine, Prevention Magazine, The Newshour, ABC World News, the NBC Nightly News, the CBS Evening News, and NPR’s Science Friday.

She was included as one of TIME Magazine’s 100 Most Influential People of 2016, and she also received the 2018 Giant of Cancer Care® in Cancer Diagnostics award.

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Research Area: To characterize the tumor microenvironment to identify strategies to improve outcomes for breast cancer patients.

Impact: Immunotherapy is a promising treatment for breast cancer, but currently few patients benefit from it. Identifying those patients that are responsive to immunotherapy would inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman and her team demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. Their work has also shown, however, that other immune factors play a role in suppressing anti-tumor immune activity. In her current BCRF research, Dr. Esserman is utilizing novel imaging technologies to analyze the immune cell composition of the aggressive tumors found in women of African descent. Results from this work will inform more effective, targeted interventions to treat these patients.

Progress Thus Far: Dr. Esserman has developed a specialized imaging technology through which they determined the spatial proximity of immune cells to tumor cells and developed  biomarkers panels specific to various immune cells. Her team has used these biomarker panels to determine their potential to predict how patients will respond to treatment, particularly patients of African descent. In the last year and in collaboration with fellow BCRF investigator, Dr. Funmi Olopade, 144 breast cancer tissue samples from African and African American women have been obtained and processed. In addition, Dr. Esserman and her colleagues have optimized and validated two new multiplex staining protocols that will enhance our understanding of the immune microenvironment of these breast cancers.

What's next:  Studies are underway to characterize the samples and immune infiltrates from the tumors samples the team has assembled. In the coming year, they will compare the resulting data from Nigerian breast cancer patients with that obtained from African American women with high-risk early stage breast cancer, data available from the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women.

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Research Area: To characterize the tumor microenvironment to identify strategies to improve outcomes for breast cancer patients.

Impact: Immunotherapy is a promising treatment for breast cancer, but currently few patients benefit from it. Identifying those patients that are responsive to immunotherapy would inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman and her team demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. Their work has also shown, however, that other immune factors play a role in suppressing anti-tumor immune activity. In her current BCRF research, Dr. Esserman is utilizing novel imaging technologies to analyze the immune cell composition of the aggressive tumors found in women of African descent. Results from this work will inform more effective, targeted interventions to treat these patients.

Progress Thus Far: Dr. Esserman has developed a specialized imaging technology through which they determined the spatial proximity of immune cells to tumor cells and developed  biomarkers panels specific to various immune cells. Her team has used these biomarker panels to determine their potential to predict how patients will respond to treatment, particularly patients of African descent. In the last year and in collaboration with fellow BCRF investigator, Dr. Funmi Olopade, 144 breast cancer tissue samples from African and African American women have been obtained and processed. In addition, Dr. Esserman and her colleagues have optimized and validated two new multiplex staining protocols that will enhance our understanding of the immune microenvironment of these breast cancers.

What's next:  Studies are underway to characterize the samples and immune infiltrates from the tumors samples the team has assembled. In the coming year, they will compare the resulting data from Nigerian breast cancer patients with that obtained from African American women with high-risk early stage breast cancer, data available from the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women.

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Research area: Utilizing biomarkers, which have been found to identify immune cells in the tumor microenvironment, to determine the response of patients to immunotherapy.

Impact: Identifying those patients that would be responsive to immunotherapy would help inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman has developed new technologies to monitor—and potentially predict—response to immunotherapies including a special imaging technology. Since there are relatively few studies that describe the tumor biology of breast cancer in African women, Dr. Esserman will utilize these technologies to analyze the immunological features of breast cancers in this population.  She and her team hope to improve our understanding of the immune composition of the aggressive tumors found in women of African descent which will help craft more effective, targeted interventions to treat these patients.

Current investigation: Utilizing previously developed techniques to identify and characterize the immunological features of breast cancers from women of African descent to help guide targeted interventions to improve outcomes for these patients.

What she’s learned so far: Dr. Esserman has developed procedures for staining breast cancer tissue to define the immune microenvironment of tumors — specifically, these procedures help identify the presence and spatial proximity of immune cells to tumor cells. Her studies have resulted in the identification of specific biomarkers for various immune cells. Moreover, the team has demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. For triple-negative tumors, having T cells near the tumor cells was the most important predictor of an excellent response to immunotherapy.  Their work has also shown that while local immunotherapy of ductal carcinoma in situ (DCIS) resulted in an expansion of immune cells within the DCIS, this did not result in reduced tumor size or cell killing – suggesting that there are other factors that play a role in suppressing anti-tumor immune activity.

What’s next: In the coming year, Dr. Esserman will apply her biomarker findings (multiplex immunofluorescence biomarker panels) to determine their predictive potential for women of African descent. In collaboration with fellow BCRF investigator, Dr. Funmi Olopade, her team will characterize the immune infiltrates of tumors from Nigerian women using these biomarkers. In addition, they will compare the resulting data from Nigerian breast cancer patients with that obtained from African American women with high risk early stage breast cancer, available from the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women.

# data[].attributes.field_full_research_summary.processed
Research area: Utilizing biomarkers, which have been found to identify immune cells in the tumor microenvironment, to determine the response of patients to immunotherapy.

Impact: Identifying those patients that would be responsive to immunotherapy would help inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman has developed new technologies to monitor—and potentially predict—response to immunotherapies including a special imaging technology. Since there are relatively few studies that describe the tumor biology of breast cancer in African women, Dr. Esserman will utilize these technologies to analyze the immunological features of breast cancers in this population.  She and her team hope to improve our understanding of the immune composition of the aggressive tumors found in women of African descent which will help craft more effective, targeted interventions to treat these patients.

Current investigation: Utilizing previously developed techniques to identify and characterize the immunological features of breast cancers from women of African descent to help guide targeted interventions to improve outcomes for these patients.

What she’s learned so far: Dr. Esserman has developed procedures for staining breast cancer tissue to define the immune microenvironment of tumors — specifically, these procedures help identify the presence and spatial proximity of immune cells to tumor cells. Her studies have resulted in the identification of specific biomarkers for various immune cells. Moreover, the team has demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. For triple-negative tumors, having T cells near the tumor cells was the most important predictor of an excellent response to immunotherapy.  Their work has also shown that while local immunotherapy of ductal carcinoma in situ (DCIS) resulted in an expansion of immune cells within the DCIS, this did not result in reduced tumor size or cell killing – suggesting that there are other factors that play a role in suppressing anti-tumor immune activity.

What’s next: In the coming year, Dr. Esserman will apply her biomarker findings (multiplex immunofluorescence biomarker panels) to determine their predictive potential for women of African descent. In collaboration with fellow BCRF investigator, Dr. Funmi Olopade, her team will characterize the immune infiltrates of tumors from Nigerian women using these biomarkers. In addition, they will compare the resulting data from Nigerian breast cancer patients with that obtained from African American women with high risk early stage breast cancer, available from the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women.

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Director, Carol Franc Buck Breast Care Center
Professor of Surgery and Radiology
Clinical Program Leader, Breast Oncology Program
Alfred A. de Lorimier Endowed Chair in General Surgery
UCSF Helen Diller Family Comprehensive Cancer Center

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If it were not for BCRF, we would not have had the funding to pursue the exploration of the tumor immune environment and the role it plays in generating response to standard chemotherapy in combination with immune checkpoint inhibitors. These insights are helping us to understand whether African and African American women have similar patterns in their tumor immune environments and how we can use these insights to personalize and optimize treatment.  - Dr. Esserman

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If it were not for BCRF, we would not have had the funding to pursue the exploration of the tumor immune environment and the role it plays in generating response to standard chemotherapy in combination with immune checkpoint inhibitors. These insights are helping us to understand whether African and African American women have similar patterns in their tumor immune environments and how we can use these insights to personalize and optimize treatment.  - Dr. Esserman

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To characterize the tumor microenvironment to identify strategies to improve outcomes for breast cancer patients.

Impact

Immunotherapy is a promising treatment for breast cancer, but currently few patients benefit from it. Identifying those patients that would be responsive to immunotherapy would help inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman and her team demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. However, their work has also shown that other immune factors play a role in suppressing anti-tumor immune activity. In her current BCRF research, Dr. Esserman is utilizing novel imaging technologies to analyze the immune cell composition of the aggressive tumors found in women of African descent. Results from this work will inform more effective, targeted interventions to treat these patients.

Progress Thus Far

Prior work has demonstrated that by understanding which immune cells are in the tumor neighborhood and how close they are to each other can predict how well tumors will respond to immunotherapy. Therefore, Dr. Esserman’s team has developed new protocols to better identify the immune components in a tumor sample. In collaboration with fellow BCRF investigator, Dr. Funmi Olopade, Dr. Esserman used her immune biomarker panel developed with BCRF support to analyze the immune microenvironment of breast tumor tissue samples from 144 African and African American women. They found distinct differences in the immune microenvironment in tumors from Black women compared to tumors from white women, though there were no differences by race in the level of PD-1 and PD-L1 molecules, which are used to predict response to immune checkpoint immunotherapy.

What's next

In the coming year, Dr. Esserman and her colleagues will expand their cohort of Black women drawing on enrollment in the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women, and the racial disparities that exist—this has the potential to increase our understanding of the spectrum of disease and the types of interventions that might improve outcomes for these women.

# data[].attributes.field_research.processed
To characterize the tumor microenvironment to identify strategies to improve outcomes for breast cancer patients.

Impact

Immunotherapy is a promising treatment for breast cancer, but currently few patients benefit from it. Identifying those patients that would be responsive to immunotherapy would help inform treatment decisions to achieve the best possible outcome for patients while avoiding unnecessary toxic side effects. Dr. Esserman and her team demonstrated that the number of immune cells (particularly T cells) and their proximity to tumor cells was associated with a good response to immunotherapy in invasive breast cancer. However, their work has also shown that other immune factors play a role in suppressing anti-tumor immune activity. In her current BCRF research, Dr. Esserman is utilizing novel imaging technologies to analyze the immune cell composition of the aggressive tumors found in women of African descent. Results from this work will inform more effective, targeted interventions to treat these patients.

Progress Thus Far

Prior work has demonstrated that by understanding which immune cells are in the tumor neighborhood and how close they are to each other can predict how well tumors will respond to immunotherapy. Therefore, Dr. Esserman’s team has developed new protocols to better identify the immune components in a tumor sample. In collaboration with fellow BCRF investigator, Dr. Funmi Olopade, Dr. Esserman used her immune biomarker panel developed with BCRF support to analyze the immune microenvironment of breast tumor tissue samples from 144 African and African American women. They found distinct differences in the immune microenvironment in tumors from Black women compared to tumors from white women, though there were no differences by race in the level of PD-1 and PD-L1 molecules, which are used to predict response to immune checkpoint immunotherapy.

What's next

In the coming year, Dr. Esserman and her colleagues will expand their cohort of Black women drawing on enrollment in the I-SPY clinical trials. The highly characterized tumors from the I-SPY clinical trials and the Nigerian cohort assembled by Dr. Olopade will provide a unique opportunity for insight into the biology of tumors that arise in African and African American women, and the racial disparities that exist—this has the potential to increase our understanding of the spectrum of disease and the types of interventions that might improve outcomes for these women.

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Learn more about Andrew Ewald at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Andrew Ewald | Researcher | Breast Cancer Research Foundation

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Learn more about Andrew Ewald at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Director, Department of Cell Biology
Professor of Cell Biology
Professor of Biomedical Engineering
Professor of Oncology and Co-Director, Cancer Invasion and Metastasis Program
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University School of Medicine
Baltimore, Maryland

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Johns Hopkins University School of Medicine

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Andrew J. Ewald earned his BS in physics from Haverford College and his PhD in biochemistry and molecular biophysics from the California Institute of Technology. He is a professor in the Departments of Cell Biology, Oncology, and Biomedical Engineering at the Johns Hopkins University School of Medicine. His laboratory has pioneered the use of 3D culture techniques to study the growth and invasion of breast cancer cells.

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Andrew J. Ewald earned his BS in physics from Haverford College and his PhD in biochemistry and molecular biophysics from the California Institute of Technology. He is a professor in the Departments of Cell Biology, Oncology, and Biomedical Engineering at the Johns Hopkins University School of Medicine. His laboratory has pioneered the use of 3D culture techniques to study the growth and invasion of breast cancer cells.

Dr. Ewald's goal is to identify the molecules driving metastatic spread to enable the development of targeted therapies. His laboratory includes basic science and medical trainees and he collaborates with both engineers and clinicians. BCRF funding is critical to his current efforts to develop strategies to identify the patients at highest risk of metastatic recurrence and to develop innovative therapies to treat patients with metastatic breast cancer.

Dr. Ewald founded the Cancer Invasion and Metastasis Research Program at the Sidney Kimmel Comprehensive Cancer Center, which brings together 40 faculty from 15 departments to understand how metastasis works and bring these insights to patient benefit. In 2021, he was appointed director of the Department of Cell Biology at Johns Hopkins Medicine. His department has historic strengths in imaging, cell migration, lipid trafficking, and cancer cell biology. Leadership of these two units enables him to bring together basic scientists, engineers, and clinicians and to apply cutting edge technologies and multidisciplinary perspectives to solve problems in breast cancer

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Andrew J. Ewald earned his BS in physics from Haverford College and his PhD in biochemistry and molecular biophysics from the California Institute of Technology. He is a professor in the Departments of Cell Biology, Oncology, and Biomedical Engineering at the Johns Hopkins University School of Medicine. His laboratory has pioneered the use of 3D culture techniques to study the growth and invasion of breast cancer cells.

Dr. Ewald's goal is to identify the molecules driving metastatic spread to enable the development of targeted therapies. His laboratory includes basic science and medical trainees and he collaborates with both engineers and clinicians. BCRF funding is critical to his current efforts to develop strategies to identify the patients at highest risk of metastatic recurrence and to develop innovative therapies to treat patients with metastatic breast cancer.

Dr. Ewald founded the Cancer Invasion and Metastasis Research Program at the Sidney Kimmel Comprehensive Cancer Center, which brings together 40 faculty from 15 departments to understand how metastasis works and bring these insights to patient benefit. In 2021, he was appointed director of the Department of Cell Biology at Johns Hopkins Medicine. His department has historic strengths in imaging, cell migration, lipid trafficking, and cancer cell biology. Leadership of these two units enables him to bring together basic scientists, engineers, and clinicians and to apply cutting edge technologies and multidisciplinary perspectives to solve problems in breast cancer

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Goal: To understand how breast cancer spreads and to identify preventive strategies to improve patient outcomes.

Impact: Dr. Ewald is studying how breast cancer cells spread through the body to form new tumors in the lungs, brain, liver, and bones. This process, called metastasis, is the major cause of cancer deaths. His findings may guide the development of new strategies to improve outcomes for women with metastatic breast cancer (MBC).

What’s next: He and his colleagues will continue to reveal how breast cancer cells metastasize and aim to identify targets within breast cancer cells that allow them to form new tumors at distant sites.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to other parts of the body. While treatable, it is currently incurable. Dr. Ewald employs sophisticated laboratory technologies to study breast cancer cells and understand the steps involved that allow them travel through the body and colonized new sites. His goal is to discover ways to prevent metastasis from occurring and to identify new molecular targets to improve outcomes for patients with MBC.

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Goal: To understand how breast cancer spreads and to identify preventive strategies to improve patient outcomes.

Impact: Dr. Ewald is studying how breast cancer cells spread through the body to form new tumors in the lungs, brain, liver, and bones. This process, called metastasis, is the major cause of cancer deaths. His findings may guide the development of new strategies to improve outcomes for women with metastatic breast cancer (MBC).

What’s next: He and his colleagues will continue to reveal how breast cancer cells metastasize and aim to identify targets within breast cancer cells that allow them to form new tumors at distant sites.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to other parts of the body. While treatable, it is currently incurable. Dr. Ewald employs sophisticated laboratory technologies to study breast cancer cells and understand the steps involved that allow them travel through the body and colonized new sites. His goal is to discover ways to prevent metastasis from occurring and to identify new molecular targets to improve outcomes for patients with MBC.

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Research area: Seeking to understand the biology of breast cancer metastasis in order to develop new therapies for breast cancer patients.

Impact: The major cause of breast cancer deaths is metastasis, the process by which breast cancer cells invade distant organs and establish new tumors there. In order to prevent this process from occurring, researchers must first identify the mechanisms that drive it. Dr. Ewald is studying metastasis at the cellular and molecular level with the goal of discovering ways to both prevent and treat metastatic breast cancer (MBC).

Current investigation: With the support of BCRF, Dr. Ewald’s laboratory has been investigating how different cell types within the body promote or inhibit metastasis and identifying the key targetable molecules within breast cancer cells that allow them to form new metastases.

What he’s learned so far: During the last year, Dr. Ewald’s lab showed how breast cancer cells: recruit molecular support from normal breast cells, collectively enter blood vessels, survive the stress of circulation through their adhesive interactions, and corrupt the immune system into helping them to grow into lethal metastases.

What’s next: Dr. Ewald will continue to leverage his collaborations with biologists, engineers, and clinicians to further deepen the understanding of the molecular mechanisms that breast cancer cells use to metastasize.

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Research area: Seeking to understand the biology of breast cancer metastasis in order to develop new therapies for breast cancer patients.

Impact: The major cause of breast cancer deaths is metastasis, the process by which breast cancer cells invade distant organs and establish new tumors there. In order to prevent this process from occurring, researchers must first identify the mechanisms that drive it. Dr. Ewald is studying metastasis at the cellular and molecular level with the goal of discovering ways to both prevent and treat metastatic breast cancer (MBC).

Current investigation: With the support of BCRF, Dr. Ewald’s laboratory has been investigating how different cell types within the body promote or inhibit metastasis and identifying the key targetable molecules within breast cancer cells that allow them to form new metastases.

What he’s learned so far: During the last year, Dr. Ewald’s lab showed how breast cancer cells: recruit molecular support from normal breast cells, collectively enter blood vessels, survive the stress of circulation through their adhesive interactions, and corrupt the immune system into helping them to grow into lethal metastases.

What’s next: Dr. Ewald will continue to leverage his collaborations with biologists, engineers, and clinicians to further deepen the understanding of the molecular mechanisms that breast cancer cells use to metastasize.

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Director, Department of Cell Biology
Professor of Cell Biology
Professor of Biomedical Engineering
Professor of Oncology and Co-Director, Cancer Invasion and Metastasis Program
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University School of Medicine
Baltimore, Maryland

# data[].attributes.field_research.value
Understanding how breast cancer spreads and to identify preventive strategies to improve patient outcomes.

Impact

The major cause of breast cancer deaths is metastasis, the process by which breast cancer cells invade distant organs and establish new tumors there. To prevent this process from occurring, researchers must first identify the mechanisms that drive it. Dr. Ewald is studying metastasis at the cellular and molecular level with the goal of discovering ways to both prevent and treat metastatic breast cancer (MBC). His findings may guide the development of new strategies to improve outcomes for women with MBC.

Progress Thus Far

Metastasis requires cancer cells to accomplish many different tasks: escaping the primary tumor, entering, and surviving within blood vessels, evading immune cells, and growing in an unfamiliar organ. Dr. Ewald’s research has shown that breast cancer cells typically accomplish these tasks as small groups of cells that are connected to each other by molecular “junctions” and found that the adhesive protein E-cadherin is required to form these junctions and for metastasis. In the past year, Dr. Ewald has further shown that tight junctions between cells prevent cancer invasion and spread, that their loss increases metastatic efficiency, and that E-cadherin plays a critical role in tumor cell survival that is independent of its role in cell adhesion.

What’s next

In the coming year, Dr. Ewald will further explore whether tight junctions are a critical defense against metastasis, which would support the clinical observation that breast tumors with low expression of tight junction proteins are more aggressive. In addition, Dr. Ewald will use genetic techniques to determine which protein binding partners of E-cadherin are essential to its role in cancer cell survival.

# data[].attributes.field_research.processed
Understanding how breast cancer spreads and to identify preventive strategies to improve patient outcomes.

Impact

The major cause of breast cancer deaths is metastasis, the process by which breast cancer cells invade distant organs and establish new tumors there. To prevent this process from occurring, researchers must first identify the mechanisms that drive it. Dr. Ewald is studying metastasis at the cellular and molecular level with the goal of discovering ways to both prevent and treat metastatic breast cancer (MBC). His findings may guide the development of new strategies to improve outcomes for women with MBC.

Progress Thus Far

Metastasis requires cancer cells to accomplish many different tasks: escaping the primary tumor, entering, and surviving within blood vessels, evading immune cells, and growing in an unfamiliar organ. Dr. Ewald’s research has shown that breast cancer cells typically accomplish these tasks as small groups of cells that are connected to each other by molecular “junctions” and found that the adhesive protein E-cadherin is required to form these junctions and for metastasis. In the past year, Dr. Ewald has further shown that tight junctions between cells prevent cancer invasion and spread, that their loss increases metastatic efficiency, and that E-cadherin plays a critical role in tumor cell survival that is independent of its role in cell adhesion.

What’s next

In the coming year, Dr. Ewald will further explore whether tight junctions are a critical defense against metastasis, which would support the clinical observation that breast tumors with low expression of tight junction proteins are more aggressive. In addition, Dr. Ewald will use genetic techniques to determine which protein binding partners of E-cadherin are essential to its role in cancer cell survival.

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Learn more about Carol J. Fabian at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Carol J. Fabian | Researcher | Breast Cancer Research Foundation

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Learn more about Carol J. Fabian at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor of Internal Medicine
Director, Breast Cancer Prevention and Survivorship Centers
Morris Family Endowed Chair in Cancer Prevention

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Carol Fabian received her MD, internal medicine and oncology training from the University of Kansas School of Medicine in Kansas City, Kansas. Dr. Fabian joined the faculty at the University of Kansas Medical Center in 1977 and currently holds the rank of Professor. She serves as the Director of the Breast Cancer Prevention and Survivorship Centers.

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Carol Fabian received her MD, internal medicine and oncology training from the University of Kansas School of Medicine in Kansas City, Kansas. Dr. Fabian joined the faculty at the University of Kansas Medical Center in 1977 and currently holds the rank of Professor. She serves as the Director of the Breast Cancer Prevention and Survivorship Centers. These centers are heavily involved in translational research in addition to providing clinical services. She leads the Cancer Prevention Research Program within the University of Kansas Cancer Center and holds the Morris Family Endowed Chair in Cancer Prevention.

Dr. Fabian pioneered the use of random peri areolar fine needle aspiration to acquire breast epithelial cells for refinement of breast cancer risk assessment. The technique is also used for evaluation of biomarkers to monitor response in early phase breast cancer prevention clinical trials: 1) weight loss in combination with omega-3 fatty acid supplementation; 2) a flaxseed lignin derivative; and 3) an aromatase inhibitor in postmenopausal women taking hormone replacement. She is also involved in clinical studies to promote health and quality of life for breast cancer survivors and serves as a Co-Chair for the Cancer Survivorship Committee of SWOG.

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Carol Fabian received her MD, internal medicine and oncology training from the University of Kansas School of Medicine in Kansas City, Kansas. Dr. Fabian joined the faculty at the University of Kansas Medical Center in 1977 and currently holds the rank of Professor. She serves as the Director of the Breast Cancer Prevention and Survivorship Centers. These centers are heavily involved in translational research in addition to providing clinical services. She leads the Cancer Prevention Research Program within the University of Kansas Cancer Center and holds the Morris Family Endowed Chair in Cancer Prevention.

Dr. Fabian pioneered the use of random peri areolar fine needle aspiration to acquire breast epithelial cells for refinement of breast cancer risk assessment. The technique is also used for evaluation of biomarkers to monitor response in early phase breast cancer prevention clinical trials: 1) weight loss in combination with omega-3 fatty acid supplementation; 2) a flaxseed lignin derivative; and 3) an aromatase inhibitor in postmenopausal women taking hormone replacement. She is also involved in clinical studies to promote health and quality of life for breast cancer survivors and serves as a Co-Chair for the Cancer Survivorship Committee of SWOG.

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Research Area: To develop strategies to prevent breast cancer in moderate- to high-risk women and to improve health and quality of life for breast cancer survivors.

Impact: Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Hormone replacement therapy (HRT) is the most effective way to reduce the vasomotor symptoms of menopause (hot flashes, flushing and night sweats), but there is concern that HRT might increase the risk of developing breast cancer, particularly in women with a higher than average risk. Duavee® (a combination of conjugated estrogen and bazedoxifene), is FDA approved for relief of hot flashes and prevention of osteoporosis. In her BCRF studies, Dr Fabian has shown that women who took Duavee® had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors all known to promote breast cancer growth. These observations suggest that Duavee® might be helpful for breast cancer prevention. Therefore, Dr. Fabian is investigating the potential use of Duavee® as a safe alternative to current hormone-based chemoprevention in women at risk of breast cancer.

Progress Thus Far: Based on the results of preclinical studies, Dr. Fabian and her colleagues have launched a multi-institution Phase II NCI-sponsored randomized clinical trial of Duavee® versus placebo to assess its effects on risk-associated biomarkers.

What's next: She and her team will continue their investigations of Duavee® and its potential use as a chemo-preventive. Building  on the results from the Duavee® trial,  Dr. Fabian will investigate similar combination approaches for primary breast cancer chemoprevention—those attractive potential candidates that may alleviate vasomotor symptoms as well as reduce risk.

# data[].attributes.field_current_research.processed
Research Area: To develop strategies to prevent breast cancer in moderate- to high-risk women and to improve health and quality of life for breast cancer survivors.

Impact: Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Hormone replacement therapy (HRT) is the most effective way to reduce the vasomotor symptoms of menopause (hot flashes, flushing and night sweats), but there is concern that HRT might increase the risk of developing breast cancer, particularly in women with a higher than average risk. Duavee® (a combination of conjugated estrogen and bazedoxifene), is FDA approved for relief of hot flashes and prevention of osteoporosis. In her BCRF studies, Dr Fabian has shown that women who took Duavee® had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors all known to promote breast cancer growth. These observations suggest that Duavee® might be helpful for breast cancer prevention. Therefore, Dr. Fabian is investigating the potential use of Duavee® as a safe alternative to current hormone-based chemoprevention in women at risk of breast cancer.

Progress Thus Far: Based on the results of preclinical studies, Dr. Fabian and her colleagues have launched a multi-institution Phase II NCI-sponsored randomized clinical trial of Duavee® versus placebo to assess its effects on risk-associated biomarkers.

What's next: She and her team will continue their investigations of Duavee® and its potential use as a chemo-preventive. Building  on the results from the Duavee® trial,  Dr. Fabian will investigate similar combination approaches for primary breast cancer chemoprevention—those attractive potential candidates that may alleviate vasomotor symptoms as well as reduce risk.

# data[].attributes.field_full_research_summary.value
Research area: Identifying ways to prevent breast cancer in moderate- to high-risk women and improving the health and quality of life for breast cancer survivors.

Impact: Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Therefore, Dr. Fabian is focused on finding a potential alternative for breast cancer chemoprevention that is safer and that will not cause these side effects. Duavee® (the combination of conjugated estrogen and bazedoxifene) is FDA approved for relief of hot flashes and prevention of osteoporosis. Dr. Fabian is conducting studies to assess the utility of Duavee® for breast cancer prevention.

Current investigation: Dr. Fabian and her team are evaluating Duavee® as a safe and effective option for women at high risk of breast cancer who cannot tolerate current endocrine-based chemoprevention agents.

What she’s learned so far: Dr Fabian’s studies have shown that women who took Duavee® had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors known to promote breast cancer growth. These observations suggest that Duavee® might be helpful for breast cancer prevention.

What’s next: Based on the results of both preclinical studies and a pilot clinical trial study, Dr. Fabian and her colleagues will launch a multi-institution, Phase II NCI-sponsored randomized clinical trial of Duavee® versus placebo to assess its effects on risk-associated biomarkers. Prior to the trial launch, they will also assess further candidate biomarkers, and the potential for using changes in MRI as a secondary biomarker in these trials. The results of these trials will assure patients and clinicians that Duavee® will not increase the risk for breast cancer and is safe to take for relief of hot flashes.

# data[].attributes.field_full_research_summary.processed
Research area: Identifying ways to prevent breast cancer in moderate- to high-risk women and improving the health and quality of life for breast cancer survivors.

Impact: Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Therefore, Dr. Fabian is focused on finding a potential alternative for breast cancer chemoprevention that is safer and that will not cause these side effects. Duavee® (the combination of conjugated estrogen and bazedoxifene) is FDA approved for relief of hot flashes and prevention of osteoporosis. Dr. Fabian is conducting studies to assess the utility of Duavee® for breast cancer prevention.

Current investigation: Dr. Fabian and her team are evaluating Duavee® as a safe and effective option for women at high risk of breast cancer who cannot tolerate current endocrine-based chemoprevention agents.

What she’s learned so far: Dr Fabian’s studies have shown that women who took Duavee® had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors known to promote breast cancer growth. These observations suggest that Duavee® might be helpful for breast cancer prevention.

What’s next: Based on the results of both preclinical studies and a pilot clinical trial study, Dr. Fabian and her colleagues will launch a multi-institution, Phase II NCI-sponsored randomized clinical trial of Duavee® versus placebo to assess its effects on risk-associated biomarkers. Prior to the trial launch, they will also assess further candidate biomarkers, and the potential for using changes in MRI as a secondary biomarker in these trials. The results of these trials will assure patients and clinicians that Duavee® will not increase the risk for breast cancer and is safe to take for relief of hot flashes.

# data[].attributes.field_job_title
Professor of Internal Medicine
Director, Breast Cancer Prevention and Survivorship Centers
Morris Family Endowed Chair in Cancer Prevention

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To develop strategies to prevent breast cancer in moderate- to high-risk women and to improve health and quality of life for breast cancer survivors.

Impact

Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Hormone replacement therapy (HRT) is the most effective way to reduce the vasomotor symptoms of menopause (hot flashes, flushing and night sweats), but there is concern that HRT might increase the risk of developing breast cancer, particularly in women with a higher than average risk. Dr. Fabian is focused on finding effective alternatives to tamoxifen and aromatase inhibitors that do not cause unwanted side effects.  In prior studies, her team showed that women that took (a combination of bazedoxifene and conjugated estrogen, BZA-CE) had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors known to promote breast cancer growth. Her team is building on these observations and testing a BZA-CE combination as safe alternatives to current hormone-based chemoprevention in women at risk of breast cancer.

Progress Thus Far

Dr. Fabian and her colleagues are conducting a multi-institution Phase II NCI-sponsored randomized clinical trial of the BZA-CE combination versus placebo to assess its effects on risk-associated biomarkers. They are also testing alcobifene, the conjugated estrogen component of BZA-CE, as a potential chemo-preventive agent that will not result in side effects as seen with tamoxifen and aromatase inhibitors. Prior to the trial launch, they identified candidate biomarkers, such as genes and their corresponding proteins that are affected by estrogen, that could be used to assess efficacy of the treatments. Automated measures of breast density and MRI as secondary biomarkers were also examined. Preliminary results indicate that, unlike tamoxifen, neither the combination nor alcobifene alone, increased the expression of biomarkers associated with endocrine resistance genes.

What's next

She and her team will continue to accrue patients into the clinical trial with BZA-CE to determine its potential use in chemo-preventive strategies. Based on their preclinical findings, they will launch a clinical trial with alcobifene alone. Results of these studies may identify more acceptable prevention strategies with fewer side effects for women at increased risk for breast cancer, as well as biomarkers to better predict which women will most likely benefit from the treatment.

# data[].attributes.field_research.processed
To develop strategies to prevent breast cancer in moderate- to high-risk women and to improve health and quality of life for breast cancer survivors.

Impact

Chemoprevention drugs such as tamoxifen or aromatase inhibitors, dramatically reduce the risk of developing breast cancer, but many women will discontinue their use due to side effects that can initiate or worsen menopausal symptoms. Hormone replacement therapy (HRT) is the most effective way to reduce the vasomotor symptoms of menopause (hot flashes, flushing and night sweats), but there is concern that HRT might increase the risk of developing breast cancer, particularly in women with a higher than average risk. Dr. Fabian is focused on finding effective alternatives to tamoxifen and aromatase inhibitors that do not cause unwanted side effects.  In prior studies, her team showed that women that took (a combination of bazedoxifene and conjugated estrogen, BZA-CE) had a reduction in breast density and breast tissue proliferation (cell growth) as well as a reduction in blood progesterone, testosterone, and IGF-1 levels—factors known to promote breast cancer growth. Her team is building on these observations and testing a BZA-CE combination as safe alternatives to current hormone-based chemoprevention in women at risk of breast cancer.

Progress Thus Far

Dr. Fabian and her colleagues are conducting a multi-institution Phase II NCI-sponsored randomized clinical trial of the BZA-CE combination versus placebo to assess its effects on risk-associated biomarkers. They are also testing alcobifene, the conjugated estrogen component of BZA-CE, as a potential chemo-preventive agent that will not result in side effects as seen with tamoxifen and aromatase inhibitors. Prior to the trial launch, they identified candidate biomarkers, such as genes and their corresponding proteins that are affected by estrogen, that could be used to assess efficacy of the treatments. Automated measures of breast density and MRI as secondary biomarkers were also examined. Preliminary results indicate that, unlike tamoxifen, neither the combination nor alcobifene alone, increased the expression of biomarkers associated with endocrine resistance genes.

What's next

She and her team will continue to accrue patients into the clinical trial with BZA-CE to determine its potential use in chemo-preventive strategies. Based on their preclinical findings, they will launch a clinical trial with alcobifene alone. Results of these studies may identify more acceptable prevention strategies with fewer side effects for women at increased risk for breast cancer, as well as biomarkers to better predict which women will most likely benefit from the treatment.

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Learn more about Zhen Fan at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Zhen Fan | Researcher | Breast Cancer Research Foundation

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Learn more about Zhen Fan at BCRFCure.org. The Breast Cancer Research Foundation seeks to advance the world's most promising breast cancer research.

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Professor of Medicine and Cancer Biology<br />
Department of Experimental Therapeutics

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The University of Texas MD Anderson Cancer Center

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Zhen Fan was awarded his medical degree in 1985 from the Medical School of Shanghai Medical University, one of China’s most prestigious medical schools, and completed additional graduate studies there in 1988. His medical residency and oncology research training were at Zhong Shan Hospital of Shanghai Medical University. In 1991, he joined Dr. John Mendelsohn's laboratory as a post-doctoral research fellow at Memorial Sloan Kettering Cancer Center and focused on studies of targeting the epidermal growth factor receptor as an approach for cancer therapy.

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Zhen Fan was awarded his medical degree in 1985 from the Medical School of Shanghai Medical University, one of China’s most prestigious medical schools, and completed additional graduate studies there in 1988. His medical residency and oncology research training were at Zhong Shan Hospital of Shanghai Medical University. In 1991, he joined Dr. John Mendelsohn's laboratory as a post-doctoral research fellow at Memorial Sloan Kettering Cancer Center and focused on studies of targeting the epidermal growth factor receptor as an approach for cancer therapy. From 1994 to 1995, he was a Research Associate in the Program of Molecular Pharmacology and Therapeutics, Sloan Kettering Institute for Cancer Research; in 1996, he joined the Memorial Sloan Kettering faculty as an Assistant Molecular Biologist in the Department of Medicine. In late 1996, Dr. Fan moved to Houston and joined the faculty of the University of Texas MD Anderson Cancer Center, starting as a tenure-track assistant professor. He is currently professor of medicine and cancer biology in the Department of Experimental Therapeutics in the Division of Cancer Medicine at MD Anderson, where he directs an independent laboratory focused on research for better understanding of cancer cell signaling and metabolism and for development of new technologies of antibody engineering and therapeutics. Dr. Fan has made considerable contributions to our understanding of regulation of cancer cell signaling in breast cancer, aimed at identifying novel targets for innovative breast cancer treatment. His research has been funded by multiple federal, state, and private sources.

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Zhen Fan was awarded his medical degree in 1985 from the Medical School of Shanghai Medical University, one of China’s most prestigious medical schools, and completed additional graduate studies there in 1988. His medical residency and oncology research training were at Zhong Shan Hospital of Shanghai Medical University. In 1991, he joined Dr. John Mendelsohn's laboratory as a post-doctoral research fellow at Memorial Sloan Kettering Cancer Center and focused on studies of targeting the epidermal growth factor receptor as an approach for cancer therapy. From 1994 to 1995, he was a Research Associate in the Program of Molecular Pharmacology and Therapeutics, Sloan Kettering Institute for Cancer Research; in 1996, he joined the Memorial Sloan Kettering faculty as an Assistant Molecular Biologist in the Department of Medicine. In late 1996, Dr. Fan moved to Houston and joined the faculty of the University of Texas MD Anderson Cancer Center, starting as a tenure-track assistant professor. He is currently professor of medicine and cancer biology in the Department of Experimental Therapeutics in the Division of Cancer Medicine at MD Anderson, where he directs an independent laboratory focused on research for better understanding of cancer cell signaling and metabolism and for development of new technologies of antibody engineering and therapeutics. Dr. Fan has made considerable contributions to our understanding of regulation of cancer cell signaling in breast cancer, aimed at identifying novel targets for innovative breast cancer treatment. His research has been funded by multiple federal, state, and private sources.

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Goal: To develop novel approaches to treat and prevent breast cancer metastasis.

Impact: Dr. Fan is investigating a new approach to treatment in which the immune system is “tricked” into perceiving breast cancer cells as influenza virus-infected cells, causing the immune system to launch an immune response to destroy them. If successful, this strategy may lead to a breakthrough in treatment and prevention of breast cancer recurrence and metastasis.

What’s next: Efforts this year are primarily focused on testing this approach in laboratory models of HER2-positive breast cancer.

Once breast cancer has spread to other tissues—a process called metastasis—it has become resistant to many therapies. Stimulating the immune system would be an effective way to reduce or even eliminate metastasis-associated breast cancer deaths. Dr. Fan is studying one such approach that may trigger the immune system to launch an immune response to destroy breast cancer cells.

# data[].attributes.field_current_research.processed
Goal: To develop novel approaches to treat and prevent breast cancer metastasis.

Impact: Dr. Fan is investigating a new approach to treatment in which the immune system is “tricked” into perceiving breast cancer cells as influenza virus-infected cells, causing the immune system to launch an immune response to destroy them. If successful, this strategy may lead to a breakthrough in treatment and prevention of breast cancer recurrence and metastasis.

What’s next: Efforts this year are primarily focused on testing this approach in laboratory models of HER2-positive breast cancer.

Once breast cancer has spread to other tissues—a process called metastasis—it has become resistant to many therapies. Stimulating the immune system would be an effective way to reduce or even eliminate metastasis-associated breast cancer deaths. Dr. Fan is studying one such approach that may trigger the immune system to launch an immune response to destroy breast cancer cells.

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Research goal: Identifying innovative new approaches to treat and prevent the spread of breast cancer.

Impact: Once breast cancer metastasizes to other tissues in the body, it has become resistant to many therapies and is incurable. Lack of response to current standard of care, including novel targeted cancer therapy, is the primary cause of deaths from breast cancer. While immunotherapy is reshaping current cancer treatment paradigms, a weak immune response in breast cancer hampers the use of it to treat this disease.

To address this challenge, Dr. Fan is investigating a way to prompt the body’s natural immunity to launch an immune response to destroy the cancer cells. This approach could reduce or even eliminate metastasis-associated breast cancer deaths.

Current investigation: He and his team are testing a strategy that “tricks” the immune system into perceiving breast cancer cells as influenza virus-infected cells, which would stimulate the immune system to attack the cancer cells. Current work is focused on testing treatment for HER2-positive breast cancer in laboratory models.

What he’s learned so far: Dr. Fan and his team have successfully developed the tools they need to test their strategy in breast cancer models.

What’s next: Dr. Fan and his colleagues will test their novel therapeutic approach to improve trastuzumab-based therapy for metastatic HER2-positive breast cancer.

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Research goal: Identifying innovative new approaches to treat and prevent the spread of breast cancer.

Impact: Once breast cancer metastasizes to other tissues in the body, it has become resistant to many therapies and is incurable. Lack of response to current standard of care, including novel targeted cancer therapy, is the primary cause of deaths from breast cancer. While immunotherapy is reshaping current cancer treatment paradigms, a weak immune response in breast cancer hampers the use of it to treat this disease.

To address this challenge, Dr. Fan is investigating a way to prompt the body’s natural immunity to launch an immune response to destroy the cancer cells. This approach could reduce or even eliminate metastasis-associated breast cancer deaths.

Current investigation: He and his team are testing a strategy that “tricks” the immune system into perceiving breast cancer cells as influenza virus-infected cells, which would stimulate the immune system to attack the cancer cells. Current work is focused on testing treatment for HER2-positive breast cancer in laboratory models.

What he’s learned so far: Dr. Fan and his team have successfully developed the tools they need to test their strategy in breast cancer models.

What’s next: Dr. Fan and his colleagues will test their novel therapeutic approach to improve trastuzumab-based therapy for metastatic HER2-positive breast cancer.

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Professor of Medicine and Cancer Biology
Department of Experimental Therapeutics

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Developing novel approaches to treat and prevent HER2-positive breast cancer metastasis.

Impact

Once breast cancer spreads to other tissues in the body—a process called metastasis—it has become resistant to many therapies and is incurable. Lack of response to current standard of care, including novel targeted cancer therapy, is the primary cause of deaths from breast cancer. While immunotherapy is reshaping current cancer treatment paradigms, a weak immune response in breast cancer hampers the use of it to treat this disease. To address this challenge, Dr. Fan is investigating a way to prompt the body’s natural immunity to launch an immune response to destroy cancer by “tricking” it into perceiving breast cancer cells as influenza virus-infected cells. If successful, this strategy may lead to a breakthrough in treatment and prevention of breast cancer recurrence and metastasis.

Progress Thus Far

Dr. Fan has developed a nanoparticle drug delivery system that works by delivering flu protein markers to breast cancer cells to activate an immune response. He successfully showed in breast cancer models that tagging metastatic breast cancer with these flu biomarkers tricks the immune system into attacking them. Dr. Fan and his team are now optimizing and scaling the manufacturing of the nanoparticles to test the technology in clinical trials.

What’s next

Dr. Fan’s objective is to create a second-generation nanoparticle platform that specifically targets HER2-positive breast cancer. He expects this novel nanoparticle to more effectively activate the immune system than the previously tested nanoparticles, thereby exerting stronger anti-tumor activity. In addition, the novel nanoparticles are more cost-effective to produce and easier to scale up in manufacturing and production, which will significantly accelerate clinical translation of the technology to benefit patients.

# data[].attributes.field_research.processed
Developing novel approaches to treat and prevent HER2-positive breast cancer metastasis.

Impact

Once breast cancer spreads to other tissues in the body—a process called metastasis—it has become resistant to many therapies and is incurable. Lack of response to current standard of care, including novel targeted cancer therapy, is the primary cause of deaths from breast cancer. While immunotherapy is reshaping current cancer treatment paradigms, a weak immune response in breast cancer hampers the use of it to treat this disease. To address this challenge, Dr. Fan is investigating a way to prompt the body’s natural immunity to launch an immune response to destroy cancer by “tricking” it into perceiving breast cancer cells as influenza virus-infected cells. If successful, this strategy may lead to a breakthrough in treatment and prevention of breast cancer recurrence and metastasis.

Progress Thus Far

Dr. Fan has developed a nanoparticle drug delivery system that works by delivering flu protein markers to breast cancer cells to activate an immune response. He successfully showed in breast cancer models that tagging metastatic breast cancer with these flu biomarkers tricks the immune system into attacking them. Dr. Fan and his team are now optimizing and scaling the manufacturing of the nanoparticles to test the technology in clinical trials.

What’s next

Dr. Fan’s objective is to create a second-generation nanoparticle platform that specifically targets HER2-positive breast cancer. He expects this novel nanoparticle to more effectively activate the immune system than the previously tested nanoparticles, thereby exerting stronger anti-tumor activity. In addition, the novel nanoparticles are more cost-effective to produce and easier to scale up in manufacturing and production, which will significantly accelerate clinical translation of the technology to benefit patients.

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