The unusual suspect

Duke and Johns Hopkins researchers discover genetic link to malignant glioma that could lead to better treatment for central nervous system cancers

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DURHAM, N.C.—Research coming out of Duke University Medical Center and Johns Hopkins University related to malignant glioma, a dangerous kind of brain tumor, may very well have made a groundbreaking mutation discovery with implications for drug discovery, clinical trials and personalized medicine.

The research, published in the Feb. 19 issue of the New England Journal of Medicine, found isocitrate dehydrogenase 1 (IDH1) mutations in more than 70 percent of astrocytomas and olidgodendrogliomas, as well as in secondary glioblastoma multiforme. Those without the IDH1 mutation had similar mutations in the closely related IDH2 gene, and these mutations decreased IDH enzymatic activity. As such, IDH mutations are likely important in initiating malignant gliomas, even though the scientists don't yet how they contribute to glioma development.

"IDH mutations appear to define a specific subtype of gliomas, so that we can plan specific treatment strategies to target this specific subtype of gliomas. Currently, for example, all glioblastoma patients are basically considered the same and are treated the same," notes Dr. Hai Yan, the study's lead author and an assistant professor in the Duke Department of Pathology. "What our studies have clearly demonstrated is that we need to start thinking about them differently. It is entirely possible, for example, that treatments that work for this specific subtype would not work for the rest of glioblastomas, or vice versa.

"This has significant implications for how we plan future clinical trials for patients with gliomas. In addition, we have now identified the very early genetic changes in the gliomas, which could serve as potential targets for drug discovery and future personalized medicine."

Yan believes the team's findings may be among the most important discoveries in genetic research related to malignant gliomas. "The results are so clear-cut," he says. "I have been doing intensive genetic studies in brain cancers for six years, and I have never seen gene mutations as striking as in this study."

In the editorial in that same issue of the New England Journal of Medicine, Dr. Craig B. Thompson notes that the Duke-Johns Hopkins study is important in part because the idea that mutations in metabolic pathways contribute to the pathogenesis of cancer has in the past been controversial.

But perhaps more importantly, "If it turns out that the mutations result in the activation of IDH1 under physiologic conditions, then this work will have identified a potential molecular target for the treatment of cancers of the central nervous system," Thompson notes, adding: "A potential benefit of identifying metabolic-enzyme mutations that are pathogenic in specific cancers is that such cancers may be susceptible to pharmacologic manipulations that are more effective and less toxic than existing therapies."

In general, improving the quality of life of glioma patients calls for novel therapeutic strategies that eradicate tumor cells while sparing functional neural tissue, Yan explains, and the fact that the product of the mutant genes are only in cancer cells, not in the normal cells, provides solid groundwork for future investigation into small molecules targeting the mutant genes and the pathways involved.

"As a tumor progresses, it selects for cells harboring particular genetic events; thus the bulk of a tumor is composed of the cells whose abnormal but unique genome has acquired mutations that allow for optimal growth and survival," Yan says.

As such, recurrent genetic mutations, such as those noted with IDH, invariably make a functional contribution to the tumor phenotype. The targeting of gene products affected by such mutations can result in the inhibition of a tumor-promoting function that is distinctly absent from healthy tissues.

"In simple words," Yan says, "the identification of IDH mutations provides a potential target for magic bullets to targeting selectively the tumor cells and sparing normal brain tissues."

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