Funded by 2017 BRCA Fund-A-Need
In addition to breast cancer, women who carry a defective copy of the BRCA2 (Breast Cancer Susceptibility) gene live with an incredibly high risk for ovarian cancer. Alterations in the BRCA2 gene can be passed down from parent to child (hereditary mutation) or may arise spontaneously (somatic mutation) in ovarian tumors. The biological role of BRCA2 is to repair damage to the human genome. However, the specific details of how defects in BRCA2 lead to ovarian cancer remain to be defined. The foundation of our collaborative research effort is to elucidate the molecular and genetic wiring that underlie this lethal malignancy. By identifying key players and pathways that drive ovarian tumor growth and treatment resistance, we can expose vulnerabilities that will guide the development of targeted therapies, novel biomarkers, and improve outcomes for patients. One of the highlights of the past two decades of research into BRCA biology was the discovery that patients can be treated with PARP inhibitors, drugs that target a specific DNA repair pathway, resulting in dramatic killing of BRCA deficient tumors. Unfortunately, not all patients respond to PARP inhibitor therapy, and some patients eventually relapse, thus detailed knowledge of the molecular mechanisms that lead to tumor formation and treatment resistance are needed. Our goal in this team-based research effort is to understand how PARP inhibitors selectively target BRCA2 deficient ovarian tumors, identify the molecular routes to PARP inhibitor resistance, and leverage these findings to impact clinical decision rules.