Novel Therapy to Inhibit IPMN Progression

Despite advances in therapeutic strategies, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. An opportunity exists to impact mortality from PDAC by preventing the development of the disease through preventing progression of one of its most important precursors, intraductal papillary mucinous neoplasm (IPMN). IPMN is a significant health problem with a high prevalence with an estimate of 6% of MRI studies obtained for other indications demonstrating IPMN(s). Although most IPMNs are quiescent, they represent a source of great anxiety for patients because of the fear of developing PDAC. Since 30% of PDACs arise from IPMNs, these lesions also represent an opportunity to intercept the development of PDAC. Therefore, is an unmet need to develop biomarkers that predict IPMN progression and strategies to intercept IPMN progression to PDAC. We have made substantial progress in developing strategies to intercept IPMN progression as illustrated in the parent grant of this supplement application which is translating discoveries from our laboratory regarding the role of a micronutrient (delta-tocotrienol (DT3)) in preventing IPMN progression in a Phase 2 prospective randomized double-blind placebo-controlled trial. Emerging studies suggest that the IPMN Tumor Immune Microenvironment (TIME) may play a critical role in a crosstalk with pancreatic ductal epithelial cells in promoting the progression of IPMN to PDAC. However, the role of specific immune cells and the underlying mechanisms driving TIME mediated IPMN progression is poorly understood. To address this knowledge gap, we propose to test the central hypothesis that crosstalk between specific immune cells and pancreatic ductal cells influence the switch from quiescent (low-grade) IPMN to aggressive (highgrade) IPMN leading to invasive PDAC. Using a combination of human patient samples and genetically engineered mouse models, as well as in vivo, in vitro, and in silico approaches, we propose to map immune cell populations and functional status around normal pancreatic duct, low-grade IPMN, high-grade IPMN, and invasive PDAC in humans (Aim 1); and define the function of immune cells at different stages of carcinogenesis in human and mouse (Aim 2). The supplement will allow Mrs. Krystal Villalobos-Ayala to receive further training in conducting basic and translational research. Her results will assist in defining the role of TIME in PDAC evolution ultimately contributing to further insights into novel immunological strategies to intercept IPMN progression to PDAC.