Abstract IA19: Exploiting DNA repair deficiencies in breast cancer using PARP inhibitors

Abstract

Abstract Epithelial cancers arise through acquisition of mutation in multiple genes causing either gain or loss of functions that give a phenotypic advantage to the affected cell and acquisition of key features of malignancy commonly described as the “hallmarks of cancer”. This acquisition of sufficient mutational burden to acquire these “hallmarks” may be accelerated by deficiency in one or more of number of partially redundant DNA repair mechanisms that have evolved to maintain genome stability. Many forms of chemotherapy and radiation therapy have long exploited tumor's relative deficiencies in the DNA damage response and in DNA repair specifically. Recently more specific inhibitors of DNA repair and DNA damage response effectors have been developed and tested in preclinical models and early phase clinical trials. These have shown proof of concept for the principle of tumor specific “synthetic lethality” where the synergistic combination of a therapeutically induced deficiency in one form of genome stability mechanism with a tumor specific constitutive defect in a mutually dependant from DNA repair leads to high specific tumor cell killing. This principle has been found to apply to the combination of small molecule induced inhibition of PARP1 and PARP2 in combination with tumor cell intrinsic defects in the homologous recombination (HR) DNA repair mechanism. A number of genes involved in HR, including BRCA1, BRCA2, ATM and PALB2 lead to elevated risk of breast cancer when mutated in the germline. The tumors that develop in these contexts have, as a result, functional defects in HR. Recent evidence has also suggested that a significant proportion of breast cancers show distinctive patterns of genome instability and changes in DNA damage induced repair protein expression phenotypes that indicate loss of function of HR DNA repair. Recent correlative biology studies in breast cancer and ovarian cancer trials show correlation between these emerging biomarkers with efficacy of platinum based chemotherapy, also known to target deficiency in HR. The further investigation of PARP inhibitors in breast cancer has been slowed by an initial focus of interest in the larger sporadic breast cancer population and the difficulties in identifying a likely maximum effect population in this wider population without robust assays for defects in the DNA damage response. Progress has also been hampered by the difficulty of finding tolerable combinations of these agents with chemotherapy. Differences have been uncovered between PARP inhibitor agents both in terms of potency and mechanisms of action related to presence or absence of trapping of PARP in complex with DNA that may differentially effect efficacy in targeting HR DNA repair defects or potentiation of DNA damaging chemotherapeutics. The small molecule Iniparib has been found to have no significant PARP inhibitory effect and in consequence the results with this agent in breast cancer should not be regarded as having tested any role for PARP inhibition in this context. Focus in late phase clinical trials of PARP inhibitors in breast cancer is currently returning to potent PARP inhibitors and the original proof of concept germline mutation carrier population. Here crucial questions may still remain around prevalence of mechanisms of acquired resistance demonstrated to occur in preclinical models through somatic reversion of mutations in BRCA1 and BRCA2, selection for loss of function of genes such as 53BP1 that stimulate alternative use of Non-homologous end-joining (NHEJ) repair and overexpression of the P-glycoprotein drug efflux transporter. In this lecture I will review the preclinical and emerging biomarker data described above and their relevance to current and imminent clinical trials exploring PARP inhibition in breast cancer. Citation Format: Andrew Tutt. Exploiting DNA repair deficiencies in breast cancer using PARP inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA19.