COX-2 Driven Pancreatic Adenocarcinoma

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DESCRIPTION (provided by applicant): As part of our studies on the role of cyclooxygenase-2 (COX-2) and its downstream prostaglandin products in cancer, we recently generated a transgenic mouse that over-expresses COX-2 under the control of a keratin 5 promoter. These mice, referred to as K5.COX-2, develop spontaneous pancreatic adenocarcinomas that have many of the same histological characteristics as the human disease. Preliminary evidence indicates that this occurs with a 100% incidence and is fatal by 6 to 7 months of age. The developing tumors are highly inflamed as denoted by the reactive stroma and infiltration of lymphocytes and macrophages. Administration of the selective COX-2 inhibitor, celecoxib, significantly extends their lifespan, suggesting that prostaglandins from COX-2 are driving the neoplastic process. Our goal is to further characterize this new model for pancreatic cancer with regard to a biological and molecular characterization of the developing tumors and the ability of natural products to alter the course of the disease. We hypothesize that natural products that have anti-inflammatory activity will reduce the severity of the disease and perhaps invasion and metastasis, thus prolonging lifespan. The specific aims are to: 1) Characterize the K5.COX-2 model with regard to the pathology, time of onset and progression of the disease, the incidence and location of metastases, the presence of K-ras or other ras mutations, and the possible activation of signaling pathways associated with prostaglandins and inflammation; 2) Determine whether natural products known to have anti-inflammatory activity (green tea polyphenols (GTP), genistein, silibinin and fish oil,) alter disease incidence, severity, metastases or lifespan. This will be correlated with biomarkers for proliferation, apoptosis and inflammation. The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies. The lack of good animal models for this disease has severely hampered research into its etiology, prevention and treatment. Because of the links between chronic inflammation, COX-2 and pancreatic cancer, the proposed work should contribute needed information on this disease.