Funded by 2017 BRCA Fund-A-Need
When an individual is born with one mutated (or abnormal) copy of BRCA1 or BRCA2, there is a high chance that they will develop cancer. Drugs called PARP inhibitors have been developed to take advantage of DNA repair deficiency in BRCA related cancer, but they do not work in all patients, and resistance to the medications frequently develops. There is a pressing need to more deeply analyze primary tumors in BRCA1/2 mutation carriers to see how often there are “subclones” that have other types of primary resistance to PARP inhibitors and other therapies. This information will be critical to rationally design new strategies that will overcome a broad spectrum of resistance mechanisms. Due to a higher burden of DNA mutations in BRCA1/2 related tumors, there is significant excitement about the prospect of using immune therapies for these cancers. However, further research is needed to understand the baseline immune status of BRCA1/2 tumors and the pathways in which the immune system can be turned ‘on’ in these tumors. We propose a novel strategy to use inflammatory and immune responses that target both sensitive and resistant cells within a tumor.
To address these important objectives, we present two integrated aims that utilize our collective expertise in cancer genomics, DNA repair, tumor immunology, and mouse models of cancer. Consistent with the goals of the Team Science Convergence Award application, researchers from multiple schools, departments and divisions at the University of Pennsylvania will work together to maximize innovation and productivity.