PARP

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.

Platinum-based concurrent chemoradiation (CRT) remains the standard treatment for patients with locally advanced, stage III non-small cell lung cancer (NSCLC). Outcomes for this large subgroup remain dismal, and no progress has been made in this area in the last three decades. Novel treatment options and predictive biomarkers to improve upon the outcome and reduce the toxicity of our current treatment paradigms are sorely needed. Our overall hypothesis is that the identification of acquired resistance pathways and synergistic targets for platinum-radiation therapy will lead to improved treatments and patient selection. We will pursue in vitro and in vivo xenograft studies to assess the synergistic role of PARP inhibition and ERCC1 modulation in the setting of CRT and will correlate these findings with a biomarker study using human tumor specimens. We will further validate YAP as a promising actionable target and will assess the interactions of concurrent chemoradiation with YAP blockade based on our preliminary data of synergy. Then, we will pursue an unbiased, functional shRNA genetic screen to identify further essential treatment resistance pathways, and carefully selected targets will be validated through a series of biochemical and functional assessment steps. The predictive value of biomarkers will be tested in retrospective cohorts of patients treated with cisplatin-radiation for locally advanced non-small cell lung cancer enrolled in our lung cancer database. Last, our unique tissue bank of pre- and post-neoadjuvant treatment specimens will be used for the identification of novel resistance markers based on modulation of expression upon neoadjuvant therapy, and functional validation of resistance biomarkers and novel treatment candidates will be pursued. These studies should provide the foundation for biomarker-driven translational and clinical studies in this area of major unmet clinical need.