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August 29, 2000

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Hopkins Reports New Chemoprevention Strategy For Colon Cancer

A team of scientists at Johns Hopkins, Howard Hughes Medical Institute, and Wyeth-Ayerst Research, has been able to prevent colon tumors in mice genetically susceptible to the disease, by using a two-drug combination. One of the drugs is an aspirin-like compound, sulindac, and the other is a newly developed chemical known as EKB-569, which inhibits a tumor-specific growth factor. The findings, reported in the September 1, 2000 issue of Nature Medicine, have potential for treating people with a similar predisposition.

Previous research at Johns Hopkins has shown that some individuals inherit defective genes that make them particularly susceptible to colon tumors, so that virtually all such patients develop colorectal cancers, often by the time they are 40 years old. "One of the major goals of current research is to develop medical approaches to limit tumor development in these patients," says Kenneth W. Kinzler, Ph.D., professor of oncology at Johns Hopkins.

In the current study, the researchers used a strain of mice that develops colorectal tumors due to a mutation very similar to one found in human patients. They treated the mice with two drugs: sulindac and EKB-569, which inhibits the cell's signaling process by shutting down response to a powerful growth factor called EGF. Colon tumors are known to produce more of these growth factors than normal cells.

The research team found that either drug used alone resulted in a decrease in tumor numbers. However, when used together, the drugs had a dramatic effect, almost completely inhibiting tumor development. Half of the mice developed no tumors at all, while untreated mice developed an average of 20 tumors each.

"Experience has taught us that drug combinations are the key to controlling diseases like cancer, and it appears that combinations may be the key to preventing cancer as well," says Bert Vogelstein, M.D., Clayton Professor of Oncology at Johns Hopkins and Investigator, Howard Hughes Medical Institute.

"Though prior work has shown that single drugs like sulindac can have some effect on tumor formation in both mice and humans, this is the first time that tumors have been completely prevented in a significant fraction of the mice," according to Christopher Torrance, Ph.D., research fellow at Johns Hopkins and Howard Hughes Medical Institute and lead author of the study. The researchers caution that clinical trials of the drug combination must take place to see if the therapy is effective in preventing colon cancer in humans. Clinical trials are expected to begin in approximately one year for patients with an inherited predisposition for colorectal cancer. To receive information on this trial when it becomes available, call the Hereditary Colon Cancer Program at 410-955-4041 or email hccregistry@jhmi.edu.

The Hopkins team discovered the gene defects responsible for the inherited syndromes known as Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colon Cancer (HNPCC), which account for approximately 3 5 percent of all colon cancers. Patients with FAP, the focus of this study, develop multiple colon polyps at a young age, have a pronounced family history of colon cancer, and nearly all will develop colon cancer if preventive measures are not taken.

In addition to Kinzler, Vogelstein, and Torrance, other participants in this research included Peta E. Jackson, Ph.D., and Elizabeth Montgomery, M.D., from Johns Hopkins; Allan Wissner, Ph.D., Maria Nunes, Ph.D., Philip Frost, M.D., Ph.D., and Carolyn M. Discafani, Ph.D., from Wyeth-Ayerst Research.

This research was funded by grants from the National Institutes of Health and Wyeth-Ayerst Research.

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