PARP1 as a novel therapeutic target in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. New strategies are urgently needed to improve clinical outcomes for SCLC patients. Recently, we identified high expression of the DNA-repair protein poly (ADP-ribose) polymerase 1 (PARP-1) in SCLC cell lines and tumors through a large-scale, proteomic profiling project. In vitro data from our group has shown that PARP inhibitors have single-agent activity in SCLC and potentiate the activity of chemotherapies that work by inducing DNA damage. Based on these results, we are conducting an investigator-initiated, Phase II clinical trial of the oral alkylating agent temozolomide (TMZ) with or without the PARP inhibitor ABT-888 for patients with relapsed SCLC. We hypothesize that PARP1’s action as an E2F1 co-activator contributes to the overexpression of multiple E2F1-regulated DNA repair proteins, resulting in resistance to chemotherapy. Thus, targeting PARP1 will decrease expression of E2F1-regulated DNA repair proteins, as well as directly inhibit PARP-mediated DNA repair, resulting in decreased cell viability and improved clinical outcomes in patients treated with TMZ and the PARP inhibitor. In the studies proposed here, we will test in vitro and in vivo sensitivity of SCLC to ABT-888 and TMZ, alone and in combination, and develop predictive biomarkers of response that will be tested in our Phase II clinical trial. The ultimate goal of this laboratory and clinical research is to develop PARP inhibitors as a novel therapy for SCLC.