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SPORE Project 4

Project 4 - THE ROLE OF INFLAMMATION IN PANCREATIC CANCER METASTASIS
                       Douglas Fearon, M.D. (CSHL) – Basic Co-Leader
                        Christopher Wolfgang, M.D., (JHU) – Clinical Co-Leader
                        Richard Burkhardt, (CSHL) – Co-Investigator

Project 4 will further investigate the role of excess IL-6 and glucocorticoid production during caloric restriction in establishing a peritumoral immunosuppressive microenvironment that suppresses spontaneous and therapy-induced intratumoral T cell responses in murine PDAC and determine whether this immunosuppression allows the progression of undiagnosed micrometastatic disease. In Aim 1, the cell source of these cytokines will be determined PDAC tissue from mouse models and patients and the effect of existing therapies that target these cells will be evaluated in combination with traditional cytotoxic agents in an innovative murine model of micrometastatic PDAC. To extend these experimental findings to human disease and provide rationale for an interventional clinical trial, an observational clinical study will be conducted in Aim 2 to determine the relationship between pre- and post-operative levels of IL-6 and cortisol and disease outcomes in patients undergoing resection. Findings will then be translated into the micrometastatic PDAC mouse model to determine the effect of these changes on micrometastatic disease and develop tractable therapies to prevent this process. On the basis of these findings, an early phase interventional clinical trial will then be conducted.

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