Developing Better Treatments for Pancreatic Cancer: Fox Chase Cancer Center Researchers Identify Two Potential Protein Targets for New Drug Therapies
NEW ORLEANS -- Researchers at Fox Chase Cancer Center in Philadelphia have identified two proteins in pancreatic cancer that may be potential targets for new, more specific drug therapies against this deadly disease. Medical oncologist Steven J. Cohen, MD, presented the study today at the 40th Annual Meeting of the American Society of Clinical Oncology in New Orleans.
Cohen and his colleagues have identified increased levels of two enzymes, FAP (fibroblast activation protein) and FAK (focal adhesion kinase) in tumor samples and surrounding tissue of pancreatic adenocarcinoma specimens.
Fibroblast activation protein appears on connective tissue, or stromal fibroblasts, supporting the foundation (stroma) of various organs in the intestinal tract. This protein enhances the ability of a tumor to grow. Focal adhesion kinase not only promotes cell growth but also helps tumor cells migrate.
"Our hypothesis was that FAP and FAK would be over-expressed in pancreatic cancer and contribute to poor outcome," Cohen explained.
The researchers analyzed 29 tumor specimens from patients who had curative surgery, comparing them to normal and borderline tumor samples. Pancreatic cancer is characterized by a dense surrounding desmoplasia, or inflammatory reaction, which they hypothesized may contribute to the poor outcome in this disease. The role of FAP and FAK in cell growth and migration made them natural subjects for investigation.
"We found that FAP is over-expressed in over 90 percent of pancreatic adenocarcinomas, with greater expression in the fibroblasts surrounding the tumor than in the distant stroma," Cohen said. "Normal pancreas specimens did not have any FAP expression.
"FAK was expressed in all tumor specimens and to a greater degree than in distant stroma. In the stromal tissue, there was a modest correlation between over-expression of FAK and FAP. This suggests that interaction between these proteins may contribute to the ability of pancreatic cancer to metastasize.
"Due to the heterogeneity of the patient samples, we did not see a clear impact of these proteins on clinical outcome such as survival," Cohen explained. "However, the selective over-expression of FAP and FAK compared to normal pancreas in and immediately adjacent to tumor suggests that these proteins are attractive novel therapeutic targets for pancreatic cancer."
Cohen added that a number of animal models have been developed to study the effects of FAP on tumor growth.
"FAP promotes tumors in immunodeficient mice, but injecting antisera that blocks the activity of this enzyme inhibits tumor growth. Since targeting FAP appears promising in these preclinical models, we believe our study shows the feasibility of developing such targeted therapy for patients with pancreatic cancer."
Pancreatic cancer is the fourth leading cause of cancer deaths in American men and the fifth leading cause in American women. An estimated 31,860 new cases of pancreatic cancer will be diagnosed in 2004 and about 31,270 Americans will die of the disease this year, according to the American Cancer Society.
Cohen received a grant from the American Cancer Society to support this research. In addition to Cohen, co-authors of the study at Fox Chase include Neal J. Meropol, MD, director of the gastrointestinal cancer program; Andre Rogatko, PhD, chairman of biostatistics; Louis M. Weiner, MD, vice president for translational research and chairman of medical oncology; molecular biologist Erica A. Golemis, PhD; medical oncologist Jonathan D. Cheng, MD and staff scientist R. Katherine Alpaugh, PhD, plus pathologist Irma Palazzo, MD, of Jeanes Hospital in Philadelphia.
Fox Chase Cancer Center, part of Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase also was among the first institutions to receive the National Cancer Institute’s prestigious comprehensive cancer center designation in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are routinely recognized in national rankings, and the Center’s nursing program has achieved Magnet status for excellence three consecutive times. Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research and oversees programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX-CHASE (1-888-369-2427).