Basser Research Center for BRCA

2013-2014 Basser Research Center Grants

Cancer Risk Reduction and Prevention

Minimizing adverse outcomes following RRSO in BRCA1/2 mutation carriers:

Susan Domchek, MD was funded to comprehensively investigate the effect of risk-reducing oophorectomy (RRSO) on a variety of health outcomes. Findings from this study will be helpful in advising patients on the best timing for oophorectomy and in establishing whether interventions to treat side effects are needed. To date, Dr. Domchek's team developed an interdisciplinary and international project to prospectively study BRCA carriers undergoing RRSO and has recruited 231 women into an extensive survey study of RRSO effects for women who have already undergone the procedure. In this grant cycle, Dr. Domchek's team will start prospective recruitment and increase the survey study response rate to 500.

Comprehensive Evaluation of Cancer Risk Modifiers in BRCA1/2 Mutation Carriers:

Timothy Rebbeck, PhD has been awarded funding to study factors that modify BRCA1/2 cancer risks in carriers to provide information that may aid women and their providers in making optimal decisions about cancer prevention strategies. Dr. Rebbeck will further focus these studies on under-represented groups. To date, Dr. Rebbeck's team has undertaken a comprehensive synopsis of factors that modify BRCA1/2-associated cancer risks such as reproductive history, exposures, and modifying genes. In this grant cycle, Dr. Rebbeck's team will extend the above analyses and focus on the recruitment and analyses of these parameters in underrepresented populations.

Development of Vaccine Targeting the Tumor Vasculature for the Prevention of BRCA-deficient Tumors:

Andrea Facciabene, PhD has been working to study and develop a potential vaccine for BRCA-related cancers that may teach the immune system to react to and destroy cancerous tissue. To date, Dr. Facciabene's lab identified the device needed to deliver the vaccine to humans, developed new DNA vectors for the vaccine to perform studies necessary to submit to FDA for trials in humans, and completed all pre-IND (investigational new drug) documentation necessary to submit to FDA. In this grant cycle, Dr. Facciabene's lab will perform safety studies in an animal model in preparation for submitting an IND to FDA for clinical trials in humans.

Predictors of Healthy Mood and Memory After Oophorectomy:

C. Neill Epperson, MD is funded to study mood and memory in BRCA carriers before and after oophorectomy to determine who is at risk for adverse responses to the surgery and to determine ways to target prevention and treatment for mood and memory problems post-oopphorectomy. Dr. Epperson will be performing two randomized clinical trials to test hormone replacement therapy and a psychostimulant medication in women who are undergoing risk-reducing oophorectomy and women who have already undergone oophorectomy.

A Zebrafish Mutagenesis Screen to Identify Genes Promote Initiation and Progression of BRCA-2 Associated Ovarian Cancer:

Michael Pack, MD is funded to identify and study mutations that occur in the development of BRCA2-related ovarian cancers in a zebrafish model. In addition to providing insight into BRCA2's role in the development of ovarian cancer, the mutations identified in the development of ovarian cancer may help define risk factors for the development of ovarian cancer in carriers, identify novel targets for anti-cancer drugs, and alter our approach to detection and treatment of BRCA2-related ovarian cancer.

A Fully Optimized CAR RNA T Cell-based therapy for BRCA Cancer Treatment:

Daniel Powell, PhD is funded to further develop a potent immune-based therapy for BRCA-related breast cancers that teaches the immune system's T-cells to attack the cancer. Dr. Powell's laboratory will focus on developing this potential therapy for trial in the clinic by exploring possible allergic responses and by developing a vector for delivering the therapy to humans in a future pilot study.

Eating and Exercise for BRCA+ Survivors: Addressing Heart and Bone Health:

Kathryn Schmitz, PhD is funded to study the efficacy of a commercially available web-based nutrition and exercise program on a novel population of breast cancer survivors who have undergone risk-reducing oophorectomy under age 45 and who have not been on hormone replacement therapy for at least 2 years. Dr. Schmitz will study cardiovascular and bone outcomes in order to provide a balanced understanding of the potential benefits of nutrition and exercise on these outcomes.

The Stone Family Award in BRCA Prevention Research: Telomerase Vaccination to Prevent BRCA1/2 Related Cancer:

David Weiner, PhD and Robert Vonderheide, MD, PhD are funded to study a prevention vaccine aimed at reducing the risk of cancer is BRCA mutation carriers. Using an enzyme called hTERT, Drs. Weiner and Vonderheide aim to develop a vaccine that teaches the body's immune system to fight BRCA-related cancers. They will perform a series of preclinical studies using several mouse models of immunoprevention that are designed to prove the immunological concept, optimize the vaccine, and provide necessary data to file an investigational new drug application with FDA, the first step towards studying the vaccine in humans.

Drs. Weiner and Vonderheide's work has been made possible by the Stone Family Award, created by Norman L. Stone, W'52 and Carol Stone to advance prevention research on BRCA1/2.

Cancer Therapy Targets and Predictors of Therapy Response

Chromatin modifying factors and BRCA1/2:

Roger Greenberg, MD, PhD has been funded to study other DNA errors present in BRCA-related cancers to determine if these errors predict response to certain therapies, towards the end of developing better chemotherapy approaches based on the specific genetic changes in BRCA-related cancers. To date, Dr. Greenberg's lab has identified molecular mechanisms that influence DNA damage responses to clinically important therapies and discovered a new BRCA1-related syndrome. In this grant cycle, Dr. Greenberg's lab will work to identify additional molecular mechanisms by which BRCA1 functions that may offer new targets for enhancing sensitivity to chemotherapies in BRCA-related cancers.

Interferon-related DNA damage resistance signature (IRDS) in BRCA mutant tumor:

Andrew Minn, MD, PhD had been funded to study how cells that surround cancers can play an important role in shaping cancer behavior. Dr. Minn's project aims to identify and understand signals that are sent from non-cancer cells to cancer cells that contribute to therapy resistance. To date, Dr. Minn's lab has uncovered how pathways that normally respond to viral infection can control treatment resistance, particularly in BRCA1-related breast cancers, and how inhibiting these pathways can improve the effectiveness of therapies. In this grant cycle, Dr. Minn will study these pathways and test a hypothesis that a step of this pathway is a potential drug target for addressing therapy resistance.

The Role of BRCA2 and Genomic Instability in Pancreatic Cancer Metastasis:

Ben Stanger, MD, PhD is funded to study the role of BRCA2 in the development of pancreatic cancers, specifically the role of BRCA2 in metastatic disease. Dr. Stanger's team will use mice models to study the role of BRCA2 in pancreatic cancer and to determine whether BRCA2 mutations and mutations in a related gene called PALB2 increase sensitivity to inhibitors of other molecular pathways.

Functional Genetic Approaches to Identify MicroRNAs Regulating BRCAness in Breast and Ovarian cancer:

Lin Zhang, MD is funded to study the role of microRNA's- which are molecules that affect the action of genes - in the development of cancer and the sensitivity of cancers to chemotherapies. Dr. Zhang's team aims to identify the microRNAs present that make cancers exhibit features of BRCA-related cancers ("BRCAness"), to predict sensitivity to chemotherapies including PARP inhibitors, and to develop well-annotated databases of breast and ovarian cancers for BRCA researchers.

Effects of AURKA and BRCA1 Dysregulation on Replication Fork Stability and Cell Survival Upon ATR/CHK1 Inhibition:

Eric Brown, PhD is funded to study pathways involved in the development and drug-susceptibility of cancers that are related to BRCA1. AURKA and ATR/CHK1 are both pathways that are highly relevant in breast cancers. By studying the role of different pathways, Dr. Brown's team aims to translate their findings into potential uses of pathway-inhibitors in breast cancers that are BRCA1-deficient.

Whole genome sequencing of breast and ovarian cancers associated with BRCA1/2 mutations:

Kate Nathanson, MD, has been funded to sequence the DNA of breast and ovarian tumors for BRCA1/2 carriers to understand the molecular changes that may represent new targets for treatment or predict drug sensitivity or resistance to current regimens. To date, Dr. Nathanson's lab has identified multiple changes in 48 known cancer genes that are likely driving the growth of BRCA-related tumors and changes which suggest sensitivity to a range of experimental drugs. In the next cycle, Dr. Nathanson's lab will expand their analysis to explore thousands of gene mutations in BRCA-related tumors in the hopes of identifying novel pathways and drug targets in BRCA1 and BRCA2 mutated tumors.

Early Detection

Blood-borne biomarkers of dysplasia and early cancer in patients with BRCA mutations:

Dr. Andrew Rhim's laboratory recently found that cells from the pancreas (and other organs) can enter the bloodstream when a pre-cancerous lesion is present but long before a tumor has formed. Dr. Rhim's work focuses on applying this discovery of circulating epithelial cells (CEC's) to develop a screening method for detecting BRCA-related cancers early. To date, Dr. Rhim has initiated serial blood sampling in BRCA carriers treated at the Basser Research Center for BRCA and has detected CEC's in BRCA mutation carriers without clinical diagnoses of cancer. In this grant cycle, Dr. Rhim will continue to follow BRCA carriers with serial blood sampling to determine if CEC's can be used to identify patients with early cancer. In addition, Dr. Rhim's team will profile the genetic make-up of these cells to gain more information about their potential to develop into cancer.

Imaging Biomarkers for Risk Reduction Management of BRCA 1/2 Carriers:

Despina Kontos, PhD is funded to study whether dynamic contrast enhanced- MRI (DCE-MRI) provides useful information about the actual effect of risk-reducing methods on breast cancer risk. If DCE-MRI helps to predict which women are benefiting from each risk-reducing intervention, Kontos' team will provide new clinical decision-aid tools for improving risk-reduction and quality of life for BRCA carriers.

Next Generation Tomosynthesis Imaging for BRCA1/2 Carriers:

Andrew Maidment, PhD, FAAPM is funded to study digitial breast tomosynthesis (DBT), a novel imaging modality that may replace mammography in the future. DBT is currently limited to the detection of non-calcified lesions which is problematic because many cancers detected in BRCA2 carriers have cancers that present as calcified lesions. Dr. Maidment's team aims to develop the next generation of DBT systems that may benefit BRCA mutation carriers by increasing early detection of BRCA-related breast cancers.

Communication and Risk Assessment

REACH: Research to evaluate adolescents and early communication of hereditary risk

Dr. Angela Bradbury was awarded Basser funding to study communication about hereditary cancer risk within families, with a focus on adolescents. Her work aims to inform interventions that increase preventative behaviors and minimize adverse psychological outcomes in adolescents and young adults from BRCA families. To date, Dr. Bradbury's team reached 141 interviews with parents reporting on communication with 287 children, and also enrolled girls aged 11-19 years for interviews on knowledge and beliefs about breast cancer risk. During this grant cycle, Dr. Bradbury's team aims to complete recruitment, analyze the relationship between what parents tell their children and the psychosocial adjustment of children, and begin to develop psychosocial interventions.

AFFIRM: Assessment of Fertility and Factors Influencing Reproduction and Menopause in BRCA Mutation carries

Clarisa Gracia, MD, MSCE is funded to study the impact of carrying a BRCA mutation on fertility and reproductive decisions. BRCA mutation carriers and a control group of BRCA negative women will be recruited to provide a blood spot for hormone level testing and to complete a questionnaire on fertility and the impact of BRCA on reproductive decision-making.

Jordan Center Rena Rowan Breast Center MacDonald Womens Cancer Risk Cell & Vaccine Production Ovarian Cancer Research Breast Cancer Research Program Center for Personalized Medicine Translational Research Program BRC 4 BRCA