Defining Epigenetic Precision Medicine Therapies for Genotype- and Subtype-specific Lung Cancers

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer worldwide - this year, NSCLC will claim the lives of over 170,000 individuals in the United States alone. Current treatment options such as chemotherapies have been ineffective at eliciting long-term lung tumor regression, but targeted therapies, including those targeting epigenetic programs, offer new hope for achieving durable treatment response. Despite the excitement surrounding epigenetic therapies, how epigenetic programs influence crucial aspects of lung tumorigenesis remains an uncharted area. Clinically important is finding methods to incorporate epigenetic inhibitors to treat established lung tumors. The subtype (or epigenetic state) as well as the genotype of the tumors will likely be important biomarkers for epigenetic drug efficacy. Therefore, in Aim 1, I will use primary tumors from genetically engineered mouse models (GEMMs) of lung cancer to explore the effects of inhibitors of LSD1and UTX on tumor cell growth, differentiation and response to other chemotherapies. I will explore the effects of these drugs on Kras/p53-null and EGFR driven adenocarcinomas, the mixed Kras/Lkb1-null adenosquamous tumors, and the Lkb1-null/Pten-null squamous tumors. I previously uncovered a synergy between EZH2 inhibition and the chemotherapy etoposide in EGFR-driven tumors and will use that combination as a control. In Aim 2, I will use patient derived tumor tissue to further validate any subtype/genotype correlation to epigenetic therapy response. My research strategies will progress our knowledge of epigenetic hierarchies both within normal lung tissue and lung cancer, and will help determine clinically applicable ways to incorporate epigenetic therapies for the disease of NSCLC.