Role of Chromatin on PARP Inhibitor Responses in BRCA-Mutant Ovarian Cancer

Project summary

Mutations in genes involved in the BReast CAncer (BRCA)-dependent DNA repair pathway represent approximately 50% of high-grade serous ovarian carcinoma. This ovarian cancer type is one of the most aggressive and difficult malignancies to treat. Precision medicine based on Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated promising clinical efficacy but the inevitable emergence of resistance and associated adverse side effects have limited the benefits of this therapy. Therefore, there is a pressing unmet clinical need to develop ways by which PARPi cytotoxicity and resistance can be mitigated. We have shown that depletion of an enzyme, Amplified in Liver Cancer 1 (ALC1), can hyper-sensitize BRCA-mutant ovarian cancers to PARPi. Here, we will use ALC1-deficient BRCA-mutant cancer cells to (i) identify features that can be leveraged to enhance the efficacy of PARPi and (ii) map genome regions impacted by PARPi-based therapies. Our results can help develop an innovative and promising framework to improve and predict outcomes of PARPi therapy for the high-risk group of women with BRCA-mutations who have limited therapeutic options.

This grant was made possible in part by a generous donation from an Anonymous donor.