SUMMARY Our proposal will develop the largest cohort of Adenosquamous cancer of the pancreas (ASCP) models and characterize the genomic and epigenomic landscapes of this devastating tumor in comparison with that of pancreatic ductal adenocarcinoma (PDAC), with the expectation of identifying epigenetic features that can be exploited to selectively impair growth of cells of one or both subtypes. ASCP is a rare subtype of pancreatic cancer representing 2-4% of all pancreatic cancers with an incidence rate of < 1 case per 100,000 people per year. Strikingly, ASCP displays a higher metastatic potential and a worse clinical outcome than the more common (90-95% of cases) PDAC. Yet, a large population-based analysis did not detect any differences in tumor stage at the time of diagnosis between PDAC and ASCP. Despite aggressive surgical management for those few patients who present with resectable disease, the median survival has been reported to be consistently less than 1 year. Furthermore, no standard adjuvant therapy, or first line therapies for metastatic patients, has been established for this aggressive subtype of pancreatic cancer. Our preliminary observations suggest a unique ASCP genomic and epigenomic landscape and demonstrate how our molecular studies can identify candidate therapeutic targets and strategies for this dismal cancer that we now aim to validate using unique preclinical ASCP models. It is our HYPOTHESIS that ASCP evolve from the same lineage as PDACs yet contain distinct epigenomic features driving the aggressive phenotype of ASCP. We propose that modulating ASCP epigenome will sensitize ASCP cells to existing chemotherapies (e.g., gemcitabine and irinotecan) used as first line of treatments for PDAC and other solid malignancies. Further, we will evaluate the effects of depletion of key epigenetic proteins on the maintenance of the ASCP epigenome and cell viability, and the impact of epigenetically targeted drugs in combination with chemotherapeutic agents on ASCP tumor growth with the aim of identifying precision treatments for ASCP. Our studies will provide insight into the epigenetic mechanisms that maintain the ASCP and PDAC phenotypes and will be relevant to squamous carcinomas from other tissues (e.g., colon, lung and stomach). Further, the successful completion of this proposal will serve as a foundation for new treatment options for ASCP patients and potentially other cancers with mixed histologies.