Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Mostof the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die withina year of diagnosis. There is an urgent a need to develop new and better strategies for the treatment ofpancreatic cancer. This will require novel approaches to both chemoprevention and chemotherapy, andphytochemicals offer to possibilty of this. For a cancer cell to develop an alteration in the cellular metabolicprofile must occur. Once the normal pancreatic cell has converted to an cancer cell, then a group of cancercells must recruit additional blood supply to grow and metastasize - a process is termed the angiogenicswitch. We and others have found that genistein, a flavonoid, may be a useful approach in impacting themetabolic profile of the pancreatic cancer cell and may inhibit the factors stimulated by the angiogenicswitch. Preliminary evidence in our laboratory suggests that genistein can alter the pancreatic cancer cellmetabolic profile, inhibit cell growth, induce apoptosis, diminish metastatic spread in vivo, and decreaseangiogenesis. We hypothesize that flavonoids prevent the progression to pancreatic cancer, and thatflavonoids may act as a chemotherapeutic in established pancreatic cancer. We will pursue the followingspecific aims:
Specific Aim I). Determine the ability of flavonoids to prevent the progression of pancreaticintraepithelial neoplasia (PanIN) to invasive pancreatic ductal adenocarcinoma using a novel transgenicpancreatic cancer animal model.
Specific Aim II). Assess the effect of flavonoids on immortalized humanpancreatic cancer cell lines in an orthotopic xenograph model.
Specific Aim III). Determine the impact offlavonoids in patients with pancreatic cancer. To complete these aims we will perform experimentsinvestigating genistein, quercetin, and apigenin in a transgenic model (LSL-KRAS G12D;PDX-1-Cre) thatrecaputulates premalignant and malignant pancreatic lesions. Also we will test these flavonoids in anorthotopic murine model and compare these to standard gemcitabine treatment. Finally, we will takeadvantage our large clinical volume of patients with pancreatic cancer and study the impact of soysupplementation in patients with this disease.
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