Project 2: Combination PARPi-BETi to Overcome PARPi Resistance

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ABSTRACT – PROJECT 2 PARP inhibitors have emerged as an established standard of care option in epithelial ovarian cancer (OvCa). Approximately half of OvCa patients harbor inactivating genetic alterations in the homologous recombination (HR) pathway, which results in synthetic lethality with PARP inhibition (PARPi). PARPi have promising activity in HR-deficient OvCa. Even though less effective compared to HR-deficient OvCa, PARPis have also been shown to be active in HR-proficient OvCa. Unfortunately, the activity of PARPi is limited by the emergence of PARPi resistance. Therefore, there is an urgent need to identify potential strategies to reverse PARPi resistance in OvCa. Our preliminary studies suggest that inhibition of BRD4 activity by bromodomain extraterminal inhibitors (BETi) is an attractive approach to reverse PARPi resistance. Notably, the BRD4 genomic locus 19p13.12 is often amplified in high-grade serous OvCa (~20%). Indeed, BRD4 amplification/overexpression correlates with a poor prognosis in these patients. We and others have shown that BETis play a major role in suppressing the HR pathway and impairing the G2/M checkpoint, which reverses resistance to PARPi caused by restoration of the HR pathway. Therefore, our central hypothesis is that targeting BRD4 activity using clinically applicable BET inhibitor is sufficient to overcome resistance to PARPi developed in recurrent OvCa. We also hypothesize that targeting BRD4 will sensitize tumor to PARPi by simultaneously downregulating HR activity, specifically BRCA1, RAD51 and TOPBP1 expression, and impairing the G2/M phase of the cell cycle by suppressing WEE1 activity, leading to DNA damage accumulation and mitotic catastrophe. Accordingly, the objective of the present study is to evaluate the safety and efficacy of a combination of PARPi and BETi in recurrent PARPi-resistant platinum-sensitive OvCa. We also plan to assess the impact of PARPi-BETi combination on functional HR activity and percent reduction compared to baseline and correlate with objective response to therapy. Further, we plan to investigate the mechanistic basis of these findings in patient-derived models obtained from the patients enrolled in the trial. To achieve that, we propose the following specific aims (SA): SA1. To determine the safety and efficacy of PARPi combined with BETi in patients with recurrent PARPi-resistant OvCa in a phase Ib clinical trial. SA2. To investigate the impact of the combined regimen on modulating HR and DNA damage response (DDR) pathways as well as G2-M cell cycle checkpoint using tissue and circulating tumor DNA samples both at baseline, on treatment and at time of progression. SA3: To investigate the mechanisms of response and resistance to the combination regimen in preclinical models. The potential impact is significant as there is an urgent need to overcome resistance to PARPi in OvCa. This project investigates a novel new therapeutic direction combining PARPi with epigenetic therapy by BETi. PARPi resistance is a major challenge given that PARPi are now approved in first line and recurrent settings. Further, this study will investigate predictive biomarkers, which will help identify patients who benefit from this regimen. Successful execution of this study will provide a rationale to advance this regimen into scientifically rationalized trials focused on improving the outcome of this most lethal cancer with limited treatment options.