Flavonoids in Pancreatic Carcinogenesis & Angiogenesis/Hines, Oscar

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Most[unreadable] of the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die within[unreadable] a year of diagnosis. There is an urgent a need to develop new and better strategies for the treatment of[unreadable] pancreatic cancer. This will require novel approaches to both chemoprevention and chemotherapy, and[unreadable] phytochemicals offer to possibilty of this. For a cancer cell to develop an alteration in the cellular metabolic[unreadable] profile must occur. Once the normal pancreatic cell has converted to an cancer cell, then a group of cancer[unreadable] cells must recruit additional blood supply to grow and metastasize - a process is termed the angiogenic[unreadable] switch. We and others have found that genistein, a flavonoid, may be a useful approach in impacting the[unreadable] metabolic profile of the pancreatic cancer cell and may inhibit the factors stimulated by the angiogenic[unreadable] switch. Preliminary evidence in our laboratory suggests that genistein can alter the pancreatic cancer cell[unreadable] metabolic profile, inhibit cell growth, induce apoptosis, diminish metastatic spread in vivo, and decrease[unreadable] angiogenesis. We hypothesize that flavonoids prevent the progression to pancreatic cancer, and that[unreadable] flavonoids may act as a chemotherapeutic in established pancreatic cancer. We will pursue the following[unreadable] specific aims: Specific Aim I). Determine the ability of flavonoids to prevent the progression of pancreatic[unreadable] intraepithelial neoplasia (PanIN) to invasive pancreatic ductal adenocarcinoma using a novel transgenic[unreadable] pancreatic cancer animal model. Specific Aim II). Assess the effect of flavonoids on immortalized human[unreadable] pancreatic cancer cell lines in an orthotopic xenograph model. Specific Aim III). Determine the impact of[unreadable] flavonoids in patients with pancreatic cancer. To complete these aims we will perform experiments[unreadable] investigating genistein, quercetin, and apigenin in a transgenic model (LSL-KRAS G12D;PDX-1-Cre) that[unreadable] recaputulates premalignant and malignant pancreatic lesions. Also we will test these flavonoids in an[unreadable] orthotopic murine model and compare these to standard gemcitabine treatment. Finally, we will take[unreadable] advantage our large clinical volume of patients with pancreatic cancer and study the impact of soy[unreadable] supplementation in patients with this disease.