Moreover, their findings point to genes that could be suppressed in order to make these tumors respond more readily to imatinib.

Lori Rink, Ph.D., a postdoctoral fellow in the laboratory of Andrew K. Godwin, Ph.D. at Fox Chase, presents their findings today, at the 100th Annual Meeting of the American Association for Cancer Research. The study uses tumor specimens collected as part of a Phase II trial on the use of the drug before surgical resection for GIST, which is led by the Radiation Therapy Oncology Group, a national clinical cooperative group funded by the National Cancer Institute.

"Imatinib has been the first drug that has really made a dent in GIST progression “ up to 80 percent response “ yet some GIST patients have little or no response to the drug," says Rink "We are looking to see how we can help clinicians make better decisions in applying imatinib or additional therapies to their GIST patients."

Rink and her colleagues followed 63 GIST patients in the RTOG trial, who were given imatinib before surgery for primary or recurrent tumors. Using tumor samples collected before and after the patients were given the drug, the researchers studied which genes were active in the tumors and then compared these profiles of gene expression to how well the tumors responded to short-term imatinib treatment.

According to Rink, they found a selection of 38 genes that were expressed higher in tumors that did not respond well to imatinib. Of these, they identified 20 KRAB-zinc finger genes that encode for proteins that typically act as transcriptional repressors of other genes. Ten of these genes, Rink says, are located to a single section of Chromosome 19.

"Our data indicate that if we can alter the activity of some of these KRAB-zinc finger proteins, we may be able to enhance the effectiveness of imatinib therapy," Rink says.

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"This important finding about biological function associated with prostate cancer risk demonstrates the power of genome-wide association studies to provide new and unexpected insights into the genetic underpinnings of cancer etiology," said Joseph F. Fraumeni, Jr., M.D., director of the Division of Cancer Epidemiology and Genetics.

Prostate cancer is the most common cancer in men, excluding skin cancer, and the second leading cause of cancer-related death in men in the United States. African American men have the highest risk of developing this disease compared with men of other racial and ethnic groups. Most of the CGEMS genome-wide association study data are from white men. The Yeager team is currently working with other researchers to evaluate whether the SNP is also associated with prostate cancer among other ethnic groups.

In addition to Yeager, the study was led by Stephen Chanock, M.D., also of DCEG and Michael Dean, Ph.D., and Hong Lou, Ph.D., of NCI's Center for Cancer Research.

For more information on NCI's Cancer Genetic Markers of Susceptibility (CGEMS) initiative, please visit cgemsncer.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at cancer or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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