Abstract SY06-03: Development of novel therapeutic strategies to target the DNA damage response in the clinic

Abstract

Abstract The clinical benefit observed with PARP inhibitors, and their subsequent regulatory approval in multiple tumor indications, have provided clinical proof of concept for a synthetic lethal approach in molecularly selected tumors and beyond. Now, we need to build on the success of such first generation PARP inhibitors through the use of rational evidence-based biomarker-driven strategies in the clinic. We can potentially accomplish this through the development of novel potent PARP1-selective inhibitors, which may lead to an improved therapeutic index and patient benefit, and the development of rational PARP inhibitor combinations with other molecularly targeted agents or immunotherapeutics, taking in consideration potential supra-additive toxicities. Finally, given recent advances in drug discovery efforts, we now have the opportunity to go beyond PARP by drugging other key DNA Damage Response (DDR) targets in the clinic, including ATR, WEE1, DNA-PK, RAD51, POLQ and USP1. I will discuss the progress we have made in the clinic, the potential pitfalls, and the promise that such novel approaches hold in improving patient outcomes. Citation Format: Timothy A. Yap. Development of novel therapeutic strategies to target the DNA damage response in the clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY06-03.