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Researchers Discover Protein Defect Linked to Gastrointestinal Cancer

   Portland, Ore.

Study identifies potential target for "smart bomb" cancer treatments

In a study to be published January 9 on the journal Science Web site, researchers have discovered a protein defect that triggers some cases of a deadly gastrointestinal cancer.

The defective protein, a mutated form of the enzyme platelet-derived growth factor receptor alpha (PDGFRA), may serve as a target for new "smart-bomb" therapies against gastrointestinal stromal tumors (GIST). "PDGFRA is found in many body tissues, so it also will be important to determine whether mutations in this enzyme might play a role in other cancers," said author Michael Heinrich, M.D., associate professor of medicine at the Portland VA Medical Center and Oregon Health & Science University Cancer Institute. Heinrich is the study's co-principal investigator with Christopher Corless, M.D., Ph.D., of the Portland VA and OHSU Cancer Institute, and Jonathan Fletcher, M.D., of Harvard Medical School.

Researchers previously had reported that an abnormal form of the enzyme KIT triggered about 85 percent of GISTs, but the cause in other cases remained unclear. Using a novel molecular technology, Heinrich and his colleagues found that 14 of 40 (35 percent) GIST tumors lacking KIT mutations instead had mutations in the related receptor tyrosine kinase, PDGFRA. Tumors expressing abnormal KIT or PDGFRA proteins were indistinguishable in cellular changes that drove tumor growth.

These findings not only show that two separate mutant proteins apparently can trigger the same cancer, Heinrich said, but validate that the technology used to detect them--or related methods--can be used to find additional targets for a whole new generation of cancer treatments. "We think the future of cancer treatment is targeted therapy that impacts cancer cells and not normal cells," said Heinrich. "First, however, we have to identify these targets, and in most cancers we don't yet know what they are."

Each year, 5,000-10,000 Americans are stricken with GISTs, which invade the organs or linings of the gastrointestinal tract. Once these tumors spread, they prove unresponsive to conventional treatments and are always fatal, Heinrich noted. Heinrich and his colleagues had been studying KIT receptor tyrosine kinase for years when they became interested in a new drug that was producing astounding remissions in clinical trials with patients suffering from chronic myelogenous leukemia, a blood cancer. The drug, Gleevec, had been developed by Novartis in collaboration with OHSU researcher Brian Druker, M.D. It targeted a mutated enzyme driving the uncontrolled growth of white blood cells. Because this enzyme is structurally similar to KIT, Heinrich's team speculated that Gleevec might also inhibit the KIT enzyme.

After successful tests in the laboratory, Heinrich and OHSU/VA investigator Charles Blanke, M.D., led a multi-center study that found a majority of patients with GISTs responded well to Gleevec.

Still, researchers are puzzled by the molecular defect causing some GISTs to resist Gleevec, Heinrich noted. A new OHSU/VA study is near completion to determine Gleevec's effectiveness against GISTs caused by abnormal PDGFRA rather than KIT. In the laboratory, Heinrich and colleagues also are exploring other protein defects that may cause some GIST cases, potential new drugs to target the PDGFRA mutation and the possible role of abnormal PDGFRA in other cancers.

In addition to Heinrich, Corless and Fletcher, co-authors of the Science report include Laura McGreevey, Diana Griffith, Andrea Haley and Ajia Town of the Portland VAMC/OHSU; George Demetri, M.D., of the Dana-Farber Cancer Institute and Harvard Medical School; Samuel Singer, M.D., of the Memorial Sloan Kettering Cancer Institute; and Anette Duensing, M.D., Chang-Jie Chen, Ph.D., and Christopher D.M. Fletcher, M.D., of Brigham and Women's Hospital and Harvard Medical School. Jonathan Fletcher also is affiliated with Dana-Farber and Brigham and Women's Hospital.

The research was supported by the U.S. Department of Veterans Affairs and the Janice and Michael Burke Leiomyosarcoma Research Fund.

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