Researchers at the Johns Hopkins Oncology Center uncovered a genetic alteration that appears to predict how individuals with an aggressive type of brain cancer will respond to chemotherapy.
The discovery, published in the November 9, 2000, issue of the New England Journal of Medicine, emerged from analysis of tumor samples from 47 patients with glioma, all of whom received standard treatment with the drug, carmustine. In 19 of the patients, the methyl-guanine-DNA methyltransferase (MGMT) gene appeared in a chemically altered form and 12 of these 19 had significantly better responses to chemotherapy, including regression of the tumor and increased long-term survival. This is compared with one patient of 28 with unaltered MGMT genes who responded to the chemotherapy. Patients with altered MGMT genes lived an average of 13 months longer than the other patients.
The MGMT gene is altered through a biochemical process known as methylation. The Hopkins scientists speculate that the normal, so-called unmethylated MGMT genes support repair of DNA damage, including damage caused by chemotherapy drugs, and therefore inhibits effectiveness of the drug. When the gene is altered or methylated, however, repair activity is blocked, allowing the anticancer drugs to attack the cancer cells unchecked.
The researchers currently are investigating agents that will block the MGMT gene and increase tumor sensitivity to carmustine. "The ability to detect the methylated form of the MGMT gene may provide a new way of pre-selecting some cancer therapy based on a tumor's chemical profile," says James G. Herman, M.D., assistant professor of oncology at Johns Hopkins and principal investigator of the study.
"The most exciting aspect of this research is that we can begin applying it to therapy right away," says Manel Esteller, M.D., Ph.D., research fellow at the Oncology Center and first author of the paper. "We don't have to wait for new drugs to be developed, rather we can begin more effectively tailoring the drugs we are using today," says Esteller.
"We want to caution that testing for MGMT gene methylation in brain tumors is not yet widely available," according to Herman. Virco Lab Inc. (Great Britain) has licensed the technology from Hopkins and could have a commercial test available as early as 2001.
Methylation has long been known to help regulate the expression of proteins made by genes by adding chemical molecules to genetic on/off switches, technically called promoter regions. When the gene is unmethylated, the gene turns on. When it is methylated, the gene turns off. Its role in cancer also has been well-defined, with similar methylation patterns playing a role in colon cancer, lung cancer, lymphoma, and head and neck cancers.
More than 16,000 people are diagnosed with brain cancer annually in the United States. An additional 13,000 die each year from the disease. Though rare, brain cancers are among the deadliest and most debilitating types of malignancies. Patients frequently die within months of diagnosis.
The research was funded by the National Cancer Institute.
In addition to Herman and Esteller, other researchers were Jesus Garcia-Foncillas, M.D., Ph.D., and Esther Andion, B.Sc., from the University Hospital of Navarre, Pamplona, Spain, Steven N. Goodman, M.D., Ph.D., from Hopkins, Oscar F. Hidalgo, M.D., and Vicente Vanaclocha, M.D., from the University Hospital of Navarre, and Stephen B. Baylin, M.D., from Hopkins.
Under a license agreement between the Johns Hopkins University and Virco, Ltd., Drs. Baylin and Herman are entitled to a share of royalty received by the University on sales of products embodying the technology reported in this press release. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
Materials provided by Johns Hopkins Medical Institutions. Note: Content may be edited for style and length.
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