Abstract NT-098: WINDOW OF OPPORTUNITY TRIAL: ASSESSING THE ADAPTIVE RESPONSE OF HGSOC TO PARPI FOR INFORMED COMBINATION THERAPIES

Abstract

Abstract At least 50% of high grade serous ovarian cancer (HGSOC) patients display defects in the components of the homologous recombination (HR) DNA repair pathway, which is the only high fidelity DNA repair mechanism for double strand breaks (DSB). This provides an exciting opportunity for targeted therapies using drugs such as poly (ADP-ribose) polymerase inhibitors (PARPi). PARP is an important component of the base excision repair and alternative non-homologous recombination DNA repair pathways. Therefore, inhibition of PARP enzymatic activity induces DNA damage and leads to synthetic lethality in HR defective tumors. Several clinical trials with PARPi have shown an improvement of progression-free survival in patients but have only shown a limited effect on overall survival. As for many other targeted therapies, the cancer cells rapidly adapt to the stress induced by the drug and develop resistance. Resistance can either be genomic or adaptive. In adaptive resistance the cellular networks are rewired in the absence of genomic changes to mediate resistance. To overcome this resistance, several groups, including ours, suggested the use of PARPi-based combination therapies. Several clinical trials are currently testing PARPi combinations with drugs targeting the immune checkpoint, the DNA damage checkpoint, the PI3K pathway, and the MAPK pathway. Although several of these combinations are promising, the main challenge remains in finding the right drug combination for the right patient since each tumor has the potential to adapt differently to PARPi. We thus implemented a window of opportunity trial to determine whether it is possible to identify different adaptive responses to PARPi by comparing pre and post-treatment tumor samples from multiple sites in the peritoneal cavity. We used reversed phase protein array (RPPA) analysis to measure the expression of over 300 proteins in each tumor samples and compared pathways activity in pre and post treatment samples from individual patients. We also compared the adaptive response detected in cancer patients with the one observed in cell lines. Base on pathway scores, we developed an approach to predict which combination with PARPi would be most likely to benefit a specific patient. Overall, our results indicate that the adaptive response to PARPi treatment can be detected early during treatment and that individual patients utilize different pathways to adapt to the stress induced by the drug. This study reinforces the need and opportunity for informed combination therapies to improve outcomes in this devastating disease. Citation Format: Marilyne Labrie, Tae-Beom Kim, Zhenlin Ju, Sanghoon Lee, Yiling Lu, Ken Chen, Gordon B. Mills and Shannon N. Westin. WINDOW OF OPPORTUNITY TRIAL: ASSESSING THE ADAPTIVE RESPONSE OF HGSOC TO PARPI FOR INFORMED COMBINATION THERAPIES [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-098.