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.
Using PARP Inhibitors in the Treatment of Cancer
PARP inhibitors are a promising class of cancer treatment drugs. However, some cancers are resistant to PARP inhibitors while others can become resistant to PARP inhibitors over time. CDK12 is a protein that appears to help the cancer cell resist the beneficial effects of PARP inhibitors. So, stopping CDK12 might stop the cell’s ability to resist treatment. One way to stop CDK12 could be to promote THZ-5-31-1, which is a protein that inhibits CDK12. Principal Investigator Geoffrey Shapiro, MD, PhD (Dana-Farber Cancer Institute) is funded to assess how promoting THZ-5-31-1 might stop the body from accidentally repairing breast cancer cells. Also, he will explore if pairing THZ-5-31-1 with a PARP inhibitor could stop a tumor from growing.
Predicting the Best Treatment for Each Patient
Knowing the protein make-up of a tumor can help doctors predict how an individual patient will respond to different types of cancer treatments. Principal Investigator Zoltan Szallasi, MD (Boston Children’s Hospital) is funded to establish a profile of the 53BP1 and Ku70 proteins that will help doctors predict how individual people with BRCA-associated cancers would respond to PARP inhibitors and platinum-based therapy. This will define a mutational profile measuring the relative activity of 53BP1 and Ku70 in BRCA mutant tumors, which will be an important step towards establishing a robust biomarker that reliably predicts response to platinum or PARP inhibitor based therapy in BRCA mutation carriers.
Inhibiting SIRT2 Activity to Inhibit BRCA Activity
BRCA proteins, which are made from BRCA genes, typically help in the repair of DNA damage that occurs in a cell’s life. There are other proteins, like SIRT2, that regulate how BRCA proteins perform this role in the cell. Principal Investigator David Yu, MD, PhD (Emory University) is funded to determine the significance of SIRT2’s regulation over BRCA1 protein activity and to determine if inhibiting SIRT2 might kill cells and tumors with BRCA1/BRCA2 dysregulation.
In addition, Principal Investigator Katherine Crew, MD (Columbia University) is funded to study BRCA in the Orthodox Jewish community. While it is known that 1 in 40 people of Ashkenazi Jewish descent carry a BRCA1 or BRCA2 gene mutation, the Orthodox Jewish community remains an under-studied population. Dr. Katherine Crew (Columbia University) is funded to develop a web-based decision aid, RealRisks, which is designed to improve genetic testing knowledge and accuracy of breast cancer risk perceptions, as well as self-efficacy to engage in a collaborative dialogue about BRCA genetic testing. The goal of this work is to develop a culturally-tailored decision aid for Orthodox Jewish women to enhance informed decision-making regarding BRCA genetic testing.