Carriers of a BRCA1 or BRCA2 (BRCA) mutation are disproportionately burdened by breast cancer (BC) and ovarian cancer (OC), yet their tumors have a unique biological profile that can be exploited. BRCA deficiency in tumor cells is associated with impaired homologous recombination repair (HRR) of DNA. We propose a paradigm shift in the therapeutic approach to BRCA-associated cancer and hypothesize that assaulting a tumor's weak point (diminished DNA repair capacity) is more efficient than targeting a tumor's forte (rapid cell proliferation). There are two advantages to this approach: 1) it specifically targets tumor cells that have lost BRCA function, an almost obligatory step in the development of BRCA-associated cancer, while sparing normal cells with an intact copy of BRCA, and 2) these inhibitors manifest a high therapeutic index. Poly(ADP-ribose) polymerase (PARP) is a therapeutic target that functions in base excision repair and is complementary to HRR. Carboplatin is an agent that may have significant synergistic effect with PARP inhibitors in the BRCA-deficient setting. We will conduct a randomized phase II clinical trial that will determine the effect of a new oral PARP inhibitor (ABT-888), validated in our pre-clinical work, as a single agent versus its use as a potentiator of carboplatin in a phase II randomized trial in patients with stage IV BRCA- associated breast cancer. Correlative studies will include biomarkers of response and resistance. Prospective observation of possible BRCA reversion mutations that may confer resistance to therapy by restoring HRR function is a critical opportunity for novel exploration- better understanding of mechanisms will suggest potential remedies to overcome or circumvent therapy resistance. Our clinical infrastructure is anchored by an established multi-institutional clinical trial consortium and a clinical cancer genetics network with a large cohort of women with hereditary BC and OC. Multiple additional N01 consortia and their affiliates across the country have agreed to collaborate on this study, supporting the feasibility of timely completion of this CTEP-approved trial. Future studies may include applying the lessons learned to treatment of BRCA-like breast cancers and ovarian cancer, as well as migration to more limited stage and neoadjuvant settings. Critically, by exploiting a frailty found in many tumors-DNA repair deficiencies-this innovative study proposes a cancer-relevant therapeutic strategy that may provide more effective treatments with fewer side effects for women with BRCA-associated BC. These studies are expected to lead to progressively innovative projects to further enhance efficacy of treatments and trials of interventions intelligently designed to work around barriers.
The major goal of our clinical translational enterprise is to manipulate DNA repair pathways to identify targets leading to new therapies that exploit BRCA-associated and 3BRCA-like2 HRR deficiencies in tumors. In this proposal we will test the combination of a poly(ADP-ribose) polymerase inhibitor and cisplatin combination, each an agent expected to have potential activity in women with BRCA-associated BC, and through our correlative science we will explore biomarkers of effect and mechanisms of resistance.
|Somlo, George; Frankel, Paul H; Arun, Banu K et al. (2017) Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083. Clin Cancer Res 23:4066-4076|
|Clark, Caroline C; Weitzel, Jeffrey N; O'Connor, Timothy R (2012) Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models. Mol Cancer Ther 11:1948-58|