Abstract IA20: Targeting DNA repair in cancer therapy

Abstract

Abstract Human cancer cells have genomic instability resulting from germline or acquired defects in DNA repair. One DNA repair pathway—the Fanconi anemia/BRCA pathway (D'Andrea A. N Engl J Med 2010;362:1909)—is defective in many human cancers, including breast, ovarian, and pancreatic neoplasms. Disruption of the FA/BRCA pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway-deficient tumors are hyperdependent on base excision repair (BER) and, accordingly, these tumors are hypersensitive to single-agent treatment with PARP1 inhibitors, which block BER, or with ATM inhibitors. Our research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy RD, D'Andrea A. J Clin Oncol 2006;24:3799, 2006). Each DNA repair pathway has a characteristic biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we have been able (1) to predict the sensitivity of tumors to conventional chemotherapy and radiation; (2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, ATM, and proteasome inhibitors); and (3) to screen for new small-molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA-damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. In my presentation, I will also discuss novel approaches to sensitizing triple negative breast cancers (TNBCs) and ovarian tumors (OCs) to PARP1 inhibitors. We have previously shown that exposure of these tumors to either a CDK inhibitor or a proteasome inhibitor can block homologous recombination (HR) repair and thereby sensitize the tumor cells to PARP1 inhibitor. The CDK inhibitor/PARP1 inhibitor combination has been examined in orthotopic primary TNBC and OC xenograft models. Finally, we have identified an additional PARP1-dependent DNA repair mechanism in TNBCs and OCs. This pathway is driven by a novel alternative end-joining polymerase, POLθ. These tumors are hypersensitive to inhibitors of this new pathway, suggesting a new target for DNA repair therapies. Citation Format: Alan D. D'Andrea. Targeting DNA repair in cancer therapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA20.