NY

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.