A causal relationship between inflammation and cancer development has been recognized for many years. Prostaglandins, generated by cyclooxygenase (COX) activity, play an important role in inflammation and tumor pathophysiology. Inhibitors of the inducible cyclooxygenase-2 (COX-2) isoform have been extensively studied in chronic inflammatory diseases and are now in clinical trials as therapy for solid malignancies. Although in recent years an extensive knowledge about the contribution of COX-2 in human malignancies has been accumulated, the exact contribution of COX-2 to pancreatic cancer pathophysiology and the therapeutic potential of selective COX-2 inhibitors in pancreatic cancer are not known. We hypothesize that 1) COX-2 is critical in pancreatic cancer pathophysiology (proliferation, apoptosis, invasion, angiogenesis), 2) selective COX-2 inhibition will restrain growth, invasion and angiogenesis in COX-2 expressing PaCa tumors and 3) treatment with COX-2 inhibitors in COX-2 deficient PaCa tumors results in tumor progression and a poorer prognosis. We will pursue the following specific aims. 1) Determine the role of COX-2 inhibitors and PPAR-gamma ligands on invasion and angiogenesis in human pancreatic cancer cells in vitro. Thereby, the relationship between COX-2 and PPAR-gamma in COX-2 positive and negative human pancreatic cancer cells, the effects of selective COX-2 inhibitors and PPAR-gamma ligands on invasion and angiogenesis of human pancreatic cancer cells, and the effects of selective COX-2 inhibitors on PPAR-gamma activation will be determined. 2) Determine the role of COX-2 and the effects of selective COX-2 inhibitors and PPAR-gamma ligands on pancreatic cancer metabolism. 3) Evaluation of the effects of selective COX-2 inhibitors and PPAR-gamma ligands on the growth, invasion and angiogenesis of human pancreatic cancer in vivo. The experiments will elucidate the role of COX-2 in pancreatic cancer invasion and angiogenesis, both critical for pancreatic cancer progression and metastases, and will thus provide the rationale for the therapeutic use of selective COX-2 inhibitors in patients with pancreatic cancer. We will also clarify the contribution of COX-2 to pancreatic cancer metabolism. Findings from these experiments will provide new insights into mechanism of the altered metabolism in pancreatic cancer cells and thus provide another basis for the development of agents and strategies for clinical application.
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