Vaccination to Prevent BRCA1/2-Related Cancer
Principal Investigators Robert Vonderheide, MD, DPhil and David Weiner, PhD and Co-Investigators Daniel Powell, PhD, Andrea Facciabene, MD, PhD, Katherine Nathanson, MD, E. John Wherry, PhD, and Ben Stanger, MD, PhD are funded to study the development of a novel vaccine that prevents BRCA1/2-related cancer in healthy individuals who carry BRCA1/2 mutations. As a first step toward this overall goal, this study will work to determine the clinical and immunological impact of vaccinating high-risk patients in remission after adjuvant therapy using TERT DNA with or without IL-12 DNA; optimize the generation of anti-tumor immunity in genetic mouse models of BRCA1/2-related cancers using prophylactic DNA-based vaccines, and discover new T cell antigens based tumor mutations in BRCA1/2 cancers.
Molecular Determinants of Chemo-responsiveness of BRCA Mutant Cancers
Principal Investigators Roger Greenberg, MD, PhD, Lin Zhang,MD, Andy Minn, MD, PhD, and Warren Pear, MD, PhD are funded to study the molecular basis of cell intrinsic and extrinsic mechanisms that dictate chemo-responsiveness of BRCA mutant cancers, and identify novel strategies that overcome common mechanisms of resistance. This study takes a multifaceted approach to achieve these objectives, using the combined expertise of 4 core laboratories, buttressed by strategic collaborations with basic and clinical investigators.
In addition, Principal Investigators Eric Brown, PhD and Fiona Simpkins, MD and Co-Investigators Rugang Zhang, PhD and Mark Morgan, MD are funded to determine if ovarian and pancreatic BRCA2-deficient cancers can be treated by targeting the ATR/CHK1 pathway as a primary line of therapy, or be used secondarily following the development of PARPi resistance. This study may lead to the development of new therapeutic strategies for patients with BRCA1/2-deficient cancers and could spur future Phase I/II trials evaluating ATR/CHK1 inhibition as an alternative primary treatment or secondary treatment for BRCA1/2-mutation carriers.
Mechanism Based Strategies to Overcome Resistance and Augment Response to Targeted Therapy in BRCA Mutant Cancer
Principal Investigator Junjie Chen, PhD (MD Anderson Cancer Center) leads a multi-institutional team funded to study novel mechanisms of chemotherapy responsiveness in BRCA mutant cancers and overcoming therapy resistance arising from these mechanisms. These studies will be performed at the level of basic laboratory investigation, using clinical samples from BRCA mutant breast and ovarian cancers that are naïve to therapy and in those that have acquired resistance. Achieving these objectives will allow for the development of more efficacious treatment strategies for BRCA patients.
Targeting Familial Breast Cancer with RAD52 Inhibitors
Principal Investigator Alexander Mazin, PhD (Drexel University) is funded to analyze the effect of RAD52 inhibitors in BRCA1-/- and BRCA2-/- cells alone and in combination with therapeutic drugs, analyze the mechanism of RAD52 inhibition in vitro, and develop more effective analogs of RAD52 inhibitors through a medicinal chemistry approach.
Analyses of the Genetic Interaction Between PARP2 and the BRCA1/BRCA2 Tumor Suppressors: Towards Selective PARP Inhibitors
Principal Investigator Sonia Franco, MD, PhD (Johns Hopkins University) is funded to employ a genetic approach to test the hypothesis that PARP2 has PARP1-independent functions in the suppression of genomic instability in BRCA-deficient backgrounds. This will help define the mechanisms of action for PARPi in BRCA cells, setting the stage for future development of biomarkers and more specific PARP inhibitors.
The Role of BRCA1 Isoforms in PARP Inhibitor and Platinum Resistance
Principal Investigator Neil Johnson, PhD (Fox Chase Cancer Center) is funded to identify and characterize BRCA1 isoforms that are capable of contributing to DNA repair and drug resistance. This characterization could be useful for predicting which patients will have lasting responses to PARP inhibitor or platinum therapy based on establishing relationships between specific BRCA1 mutations and the likelihood of expressing particular BRCA1 isoforms.
In addition, Principal Investigator Katherine Crew, MD (Columbia University) is funded to develop a program to screen underserved communities for BRCA mutations in the New York City area.