Editors' ChoiceCancer

Metabolites on the Brain

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Science Translational Medicine  16 Dec 2009:
Vol. 1, Issue 11, pp. 11ec40
DOI: 10.1126/scitranslmed.3000709

The announcement in May 2008 that U.S. Senator Ted Kennedy had been diagnosed with a malignant glioma probably sent people running straight to Google. Their searches returned bad news: These fast-growing brain tumors have poor prognoses. However, the results of a recent study may pave the way for a new approach in the treatment of malignant gliomas.

A high proportion of a certain class of human brain cancers display mutations in the gene that encodes cytosolic isocitrate dehydrogenase 1 (IDH1). The mutations modify the enzyme’s active site and thus block its ability to convert isocitrate to α-ketoglutarate. This key metabolic reaction results in the synthesis of NADPH, which is an essential cofactor for the production of reduced glutathione, the most important antioxidant in mammalian cells. The enhanced oxidative stress in IDH1-mutated cells might contribute to tumor formation. However, brain cancer cells carry this mutation in only one copy of the gene, which suggests that the effects of mutated IDH1 do not result from a simple loss of function.

Indeed, Dang et al. found that IDH1 mutations in brain cancer confer a new catalytic activity upon the enzyme: the ability to convert α-ketoglutarate to R(2)-2-hydroxyglutarate (2HG). When they assessed the three-dimensional structure of the mutated IDH1 protein, the authors found shifts in amino acid residue that could account for the observed changes in the enzyme's substrate preference and activity. There is reason to believe that these alterations promote malignant tumor progression. Individuals with other mutations that cause defective 2HG metabolism are known to have a higher risk of malignant brain cancer than do people without this inborn error of metabolism. Furthermore, the authors found higher concentrations of 2HG in human malignant glioma cells than in control cells, a measurement that may form the basis for a new diagnostic test for IDH1-related tumors. Also, mutated IDH1 may represent a new therapeutic target for small molecules that slow or block the metamorphosis of less harmful, low-grade gliomas into more dangerous secondary glioblastomas.

L. Dang et al., Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). [Abstract]

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