Effects of silencing RNAs for gastrin and CCK on human pancreatic cancer

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Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States and with the five- year survival rate of less than 1%, it remains the lowest of all malignancies. The reasons why the prognosis :or pancreatic cancer is poor are related to the inability to diagnose this malignancy in early stages and because of its resistance to standard chemotherapy. Our research group has been studying the mechanisms nvolving growth regulation of pancreatic cancer with the long-range goals of designing strategies for early diagnosis and treatment. We have found that growth of pancreatic cancer is in part regulated by the autocrine production of the gastrointestinal peptides gastrin and cholecystokinin (CCK) through a unique CCK receptor. Decreased expression and production of gastrin through antisense techniques significantly mpairs pancreatic cancer growth in culture and in animal models and is associated with a marked reduction n tumor metastases. Recently a method to silence RNA using short hairpin RNAs has been shown to more effective than antisense techniques and has potential for therapeutic intenvention. Our team has designed, developed and optimized a pegylated cationic liposome delivery system that has the capability of delivering siRNA in a tumor-targeted modality. This grant hypothesizes that growth of human pancreatic cancer can be inhibited by decreasing the expression of the peptides gastrin and / or CCK. In order to test this hypothesis, the following specific aims are proposed: 1) Abolition of gastrin or CCK production by, and action on,. pancreatic cancer cells through silencing of CCK and gastrin expression by shRNA (small hairpin RNA) technology; 2) Analyze the gastrin/CCK shRNA expressing pancreatic cancer cells in vivo in an orthotopic mouse model for primary tumor growth and metastasis, and 3) test the effect of ceramide-incorporated liposomes designed to deliver siRNA in vitro and in vivo to pancreatic cancer cells. These studies are part of the applicant's long-term goals to apply what has been learned about growth regulation of pancreatic cancer at the cellular level to patient care. These studies are the first step in bridging the results from basic science studies into the clinical realm. If shown to be effective in the animal model, we plan to proceed to treating subjects with pancreatic cancer.