Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the UnitedStates. At the time of diagnosis most patients have metastatic disease and despite attempts to employunique combination therapies the 5-year survival remains 4%. Although important progress has been madein understanding its biology, this knowledge has not yet resulted in a substantial change in patient survivaland there is clearly a need to develop new and better strategies for the treatment of PDA. Inflammatoryprocesses are instrumental to carcinogenesis and cancer progression. Eicosanoids, formed bycyclooxygenase and lipoxygenase activity, are important bioactive lipids produced in inflammatory andneoplastic conditions. Inhibition of eicosanoid production reduces the incidence and diminishes theprogression of human cancers. Polyphenolic compounds from food sources and dietary supplements havebeen shown to possess anti-inflammatory properties via inhibition of cyclooxygenase and/or lipoxygenaseactivity. Based on data from our preliminary and the available literature, we hypothesize that polyphenoliccompounds from green tea and Scutellaria baicalensis (SB): 1) inhibit proliferation and eicosanoid productionin PDA cells; 2) lower the risk of developing PDA (preventive effect); and, 3) reduce the growth and spreadof established PDA (therapeutic effect). We will study mechanisms of green tea (polyphenon E) and SBpolyphenol action on proliferation, apoptosis, and cell cycle regulation in vitro as well as using stable isotopebaseddynamic metabolic profiling (SIDMAP) technology to evaluate the overall phenotypic effect ofpolyphenols on PDA cells. In addition we will use mouse models to determine if polyphenon E and SB oncan inhibit pancreatic carcinogenesis in a transgenic model of PDA (prevention model) and reduce PDA cellgrowth in the orthotopic xenograft model (treatment model). A unique aspect of our proposal is to use stableisotope-based metabolomics approach to relate changes in metabolic flux occuring at different stages in thecarcinogenisis process in the transgenic mice. Our findings will form the rationale for future dietaryrecommendations involving phytonutrients and provide the scientific background for developing clinical trialsdesigned to evaluate the potentially therapeutic and preventive benefit of polyphenolic compounds fromgreen tea, SB, and other botanicals in PDA.
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