Resistance to targeted therapies is a major clinical challenge in the treatment of ovarian cancer. The majority of ovarian cancers have defects in repairing their DNA during cell division. Poly-ADP Ribose Polymerase (PARP) is an enzyme that is critical for DNA repair, and PARP inhibitors are generally highly effective cancer therapeutics in DNA repair-deficient ovarian cancers. However, complete and durable responses have been difficult to achieve, and the majority of the patients will relapse and develop resistance to PARP inhibition therapies. The overall goal of this project is to reveal mechanisms of PARPi resistance to find ways to identify which patients are most likely to respond to PARPi therapy, and to eventually overcome this therapy resistance.
Cancer immunotherapy has shown great promise in multiple cancers, however the responses in ovarian cancer have remained modest. It has been shown that the frequency of mutations in DNA is associated with increased response to immunotherapy. We hypothesize that PARPi will further impair DNA repair and enhance the sensitivity to immunotherapy. In this project, we will utilize unique samples from a clinical trial combining novel, effective PARPi (Niraparib) with cancer immunotherapy (PD-1 inhibitor Pembrolizumab). We will correlate the tumor characteristics to therapy outcomes in order to reveal specific markers which can be used to identify which patients will respond to PARPi + PD1 therapy.
Recent work has shown that PARPi therapy resistance can also arise from specific changes in DNA repair pathways, and by combinatorial targeting of these pathways, we may be able to overcome PARi resistance. We propose to develop new patient tumor cell-derived functional assays to evaluate these new combination treatments in individual cancers. The functional assays are first optimized with established ovarian cancer cell lines. Next, the effects on combination treatments are confirmed in mouse models. Finally, we will establish patient derived short-term tumor cell cultures from tissue samples obtained from the clinical trial testing PARPi and immunotherapy. By using these functional models, we will unravel which mechanisms contribute to PARPi resistance, and how these mechanisms can be overcome by combinatorial targeting of DNA repair.
This proposal combines my unique translational background with the vast expertise of my mentor Dr. D’Andrea in basic science and DNA repair, together with the clinical experience of by my co-mentor Dr. Konstantinopoulos at the Dana-Farber Cancer Institute. The aim is to reveal and overcome mechanisms of PARPi resistance to ultimately improve the treatment and outcomes of patients with chemoresistant, relapsed ovarian cancer.
This research has been generously supported by Ovarian Cycle Newport, RI in memory of Marilyn Bonner Feingold.