Abstract 1416: Development of small molecule inhibitors for cancer therapy by targeting RPA and XPA nucleotide excision repair proteins

Abstract Targeting DNA repair and the DNA damage response for cancer therapy has recently gained increasing attention with inhibitors of the PARP enzyme showing a therapeutic efficacy in various cancers. Solid tumors of the lung, pancreas, breast, and ovary represent a continuing clinical challenge in treatment and together account for over 250,000 deaths in the US alone, representing over 40% of all cancer deaths. There are limited therapeutic options for these patients, and targeted and combination therapies remain necessary for treating these aggressive cancers. The opportunity exists to exploit recent scientific advances in our knowledge of the underlying biology behind these cancers to create novel targeted therapeutics to dramatically enhance patient response to therapy and ultimately survival. To this end, we have developed a series of novel small chemical molecules that disrupt critical protein-DNA interactions in the nucleotide excision repair (NER) pathways. It is well understood that various cancer treatments like cisplatin, etoposide and ionizing radiation impart their chemotherapeutic effect by the formation of direct DNA damage which block DNA replication and transcription culminating in apoptosis. It is also well established that repair of this DNA damage by nucleotide excision repair (NER) or homologous recombination repair (HRR) reduces the effectiveness of chemo- or radio- therapy. Replication protein A (RPA) and Xeroderma Pigmentosum Group A (XPA) plays a crucial role in the NER pathway and makes them a novel drug target to develop novel cancer therapy. We anticipate both direct mechanisms of action on the repair pathways and synthetic lethal interactions can be exploited for therapeutic benefit. The series of novel small molecule inhibitors that we have developed targeting RPA and XPA proteins independently exhibit single-agent anti-cancer activity in cancer cell lines, and potentiate cellular sensitivity to chemotherapeutic agent. Data demonstrate that these novel inhibitors do not interact with DNA but directly bind the corresponding NER proteins. Our data demonstrate that this class of inhibitors can be further developed as an anti-cancer therapeutic with considerable potential to be used in conjunction with radiation therapy and other cancer therapies that induce DNA damage. This works was supported by NIH grants R01-CA180710 and R41-CA162648 and the Tom and Julie Wood Family Foundation. Citation Format: Navnath S. Gavande, Pamela S. VanderVere-Carozza, Tyler L. Vernon, Katherine Pawelczak, John J. Turchi. Development of small molecule inhibitors for cancer therapy by targeting RPA and XPA nucleotide excision repair proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2017-1416