PROJECT SUMMARY –OVERALL An increasing number of studies indicate that some patients with pancreas ductal adenocarcinoma (PDAC) have exceptional and durable responses to therapy, both standard of care and, more rarely to immune-based therapies. There is a unique opportunity to understand the genetic and molecular mechanisms that underlie these exceptional responses or define mechanisms of intrinsic resistance to therapy to prospectively guide clinical management and ultimately increase overall survival for all patients with pancreas cancer. We propose a Specialized Program of Research Excellence in Pancreas Cancer at Memorial Sloan Kettering Cancer Center (the MSK Pancreas SPORE) to leverage cutting-edge molecular knowledge of pancreas biology and clinical innovations to advance translational research in pancreas cancer. Our long-term translational objective is to demonstrate that prospective, next-generation molecular approaches combined with state-of-the-art clinical management can improve outcomes of patients with pancreas malignancies. We will specifically focus on the most challenging disease settings, locally advanced and metastatic PDAC, where the clinical needs are most profound. To achieve this objective, we propose three specific aims. In Aim 1, we will leverage current state-of- the-art and novel therapies to improve outcomes for patients with stage III and IV PDAC by building upon recent developments in cytotoxic and targeted therapies and apply these agents and combinations in novel disease settings. In Aim 2, we will apply innovation in molecular characterization of PDAC to drive clinical management by building upon our extensive expertise in imaging, molecular diagnostics, biomarker development, and single- cell analyses to develop and validate prospective biomarkers of treatment response and resistance. In Aim 3, we will investigate two avenues of surmounting intrinsic immunotherapy resistance in PDAC: synthetic lethality of combination PARP inhibition and immune checkpoint blockade, and via activation of the interleukin-33 – group 2 innate lymphoid cell (IL33-ILC2) axis. We expect that successful completion of these aims will provide new insights into PDAC biology, establish new collaborations, alter treatment paradigms, and ultimately improve disease-free and overall survival in pancreas cancer.