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Systematic analysis of gene family uncovers new therapeutic targets for colon cancer

Johns Hopkins Medicine

Investigators from the Johns Hopkins Kimmel Cancer Center and Howard Hughes Medical Institute have completed what is believed to be the first systematic analysis of a disease-related gene family. Their analysis, reported in the May 9, 2003 issue of Science, uncovered gene mutations, linked to more than 30 percent of colon cancers, which could serve as therapeutic targets.

The research team studied 182 human colon cancers to identify mutations in the tyrosine kinase (TK) gene family. TK genes are thought be good therapeutic targets for managing cancer because the proteins they encode play key roles in controlling cell growth, differentiation, motility, and nearby tissue invasion. Although a few TK genes have been shown to be mutated in specific cancers, until now, no study has revealed how many or how often members of the TK gene family are altered in a particular cancer type, according to Victor E. Velculescu, M.D., Ph.D., assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, who led the research effort.

"Our findings open the door to individualized analysis and treatment of colorectal cancer," says Velculescu.

TKs are so-called activating proteins that, when altered or damaged, signal cells to continually divide and take other actions that can lead to cancer. Drugs such as Gleevec, Herceptin and other inhibitor-class compounds that block the proteins made by mutated TK genes have been shown in both human clinical trials and animal studies to halt the cancer process.

"With this new work," Velculescu says, "one could imagine personalized therapeutics, based on mutations in different kinase genes and designed to match the mutated TK pathways present in each patient's particular tumor DNA."

To conduct this research, the investigators focused on the 138 normal TK genes that all humans contain. They were able to identify mutations in 14 of these genes only after sifting through more than 4 million base pairs of DNA. "These mutations are truly needles in a haystack," says Velculescu.

"Without the sophisticated new technologies and knowledge developed through the Human Genome Project, it would have been impossible for us to systematically sort through the massive amount of normal DNA sequences to find the few critical mutants," says Alberto Bardelli, Ph.D., postdoctoral fellow at the Kimmel Cancer Center and first author of the study. Similar large-scale sequencing-based approaches can now be used to identify mutations in other cancers, he says.

The researchers are now looking more closely at the TK genes most commonly mutated in the colon cancers they studied in hopes of developing new drugs to target them.

Colon cancer is the third most common form of cancer, and more than 148,000 Americans were diagnosed with this disease last year. It causes nearly 57,000 deaths annually.


This study was funded by The Benjamin Baker Scholarship Fund, The National Cancer Research Alliance, and grants from the National Institutes of Health.

In addition to Velculescu and Bardelli, other investigators included Williams Parsons, Natalie Silliman, Janine Ptak, Steve Szabo, Saurabh Saha, Sanford Markowitz, James K.V. Willson, Giovanni Parmigiani, Kenneth W. Kinzler, and Bert Vogelstein.

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