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September 4, 1998

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Hopkins Researchers Discover Key Target in Molecular Pathway that Initiates Colon Cancer

In the latest of a series of discoveries about colon cancer genes, researchers at the Johns Hopkins Oncology Center and the Howard Hughes Medical Institute have discovered a connection between two of them, APC and c-MYC, that conspires to initiate almost all colon cancers. Their findings are reported in the September 4, 1998, issue of SCIENCE.

The APC tumor suppressor gene, which acts like a brake on cell growth, loses that ability when mutated. The c-MYC gene has long been known as an oncogene, a type of gene that promotes cancer cell growth. Now, Hopkins scientists Bert Vogelstein, M.D., and Kenneth W. Kinzler, Ph.D., have found that the mutated APC gene controls the expression of c-MYC activation. APC was first identified and linked to colon cancer in 1991 by research teams including those led by Vogelstein and Kinzler.

Every person carries the c-MYC oncogene, but it remains under control in the colon until APC inactivation awakens it, generating the distinctive uncontrolled cell growth that mark cancers. "Cancer is like a car with the accelerator pushed to the floor and failing brakes," says Vogelstein, professor of oncology at Hopkins and a Hughes scholar.

"In this case, c-MYC is the accelerator and APC is the failed brakes," he explains. When suppressor genes, like APC, malfunction either through heredity or as a result of exposure to carcinogens, cells get signals to continue multiplying until they are out of control. "Now we know that in colon cancer a mutated APC gene signals to c-MYC," Vogelstein says.

The new findings about the APC pathway and how it functions may suggest potential new drug strategies that could prevent colon cancer by blocking the signal that activates c-MYC, says Kinzler, associate professor of oncology and director of the study. "Just eight years ago, we didn't even know about APC mutations. Now, we know this type of mutation is one of the earliest genetic changes in most colon cancers, and we know what it does to c-MYC. It's like a jigsaw puzzle. We have identified individual pieces of the cancer puzzle and now we can begin to put them together to see the whole picture of how they work together to cause cancer," Kinzler says. Colon cancer, among the most common cancers in both men and women, this year will strike more than 131,000 Americans. Some 56,500 individuals will die of it.

In addition to Vogelstein and Kinzler, other research participants included Tong-Chuan He, M.D., Ph.D., Andrew B. Sparks, Ph.D., Carlo Rago, B.S., Heiko Hermeking, Ph.D., Leigh Zawel, Ph.D., Luis T. Da Costa, M.S., and Patrice J. Morin, Ph.D. The study was funded by the National Institutes of Health.

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Under a licensing agreement between the Johns Hopkins University and Genzyme, SAGE technology, which was used this study, is licensed to Genzyme for commercial purposes. Kenneth W. Kinzler, Ph.D., and Bert Vogelstein, M.D., are entitled to a share of the royalty received by the University from sales of the licensed technology. The SAGE technology is freely available to academia for research purposes. Kinzler and Vogelstein are consultants to Genzyme. The University and the researchers own Genzyme stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.


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