Abstract PL04-02: Synthetic lethality: Targeting DNA repair mechanisms in clinical trials

Abstract

Abstract Epithelial carcinomas are in general diseases occurring as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone in the tissues of the primary site. In the last two decades the role of genome caretakers, which function in key areas of the DNA damage response, have been recognized as important tumor suppressor genes. Inactivating mutations in these genes occur as germline and /or as somatic mutations. In either event, loss of function in a tumor cell precursor clone leads to accelerated mutation acquisition and underpins the etiology of the tumor. As an understanding of the complex network that is the DNA damage response matures additional roles for signaling pathways, already recognized to be central to the establishment of the cancer phenotype, as controllers of DNA repair are being discovered. This has relevance to identification of wider populations of patients with tumors susceptible to approaches that target DNA repair deficiency. These have claissically been with DNA damaging chemotherapy but recently the development of small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target deficiencies in DNA repair as well as sensitize to DNA damaging therapeutics such as radiation and chemotherapy. Early-phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, Olaparib, Veliparib, Iniparib and MK4827 have all been presented. The results of the first phase II trials that explore monotherapy PARP inhibitor strategies, based on revisiting the concept of synthetic lethality, have emerged and will be reviewed. PARP inhibitors are also being explored as sensitizers to DNA damaging therapies. The phase II and III trials that have or are exploring combinations with DNA damaging therapy in these contexts will be discussed. I will then discuss biomarkers that have been proposed and are being investigated to develop optimum drug schedule and optimize patient selection for PARP inhibitor therapy approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL04-02. doi:10.1158/1538-7445.AM2011-PL04-02