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Metabolomics Study Provides Insight into Glioma-Associated Metabolic Changes

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Metabolon, Inc., has announced the publication of “Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome”, in The Proceedings of the National Academy of Sciences (PNAS 108 (8) 3270-3275). Application of non-targeted biochemical profiling (metabolomics) to mutant IDH1- and IDH2-expressing human oligodendroglioma (HOG) cells revealed altered metabolism in the cells and provided clues to the pathogenesis of tumors with IDH1 and IDH2 mutations.

The study was performed by co-authors Hai Yan and colleagues from Duke University Medical Center and Bert Vogelstein and colleagues at Johns Hopkins University School of Medicine and the metabolomic profiling was carried out at Metabolon.

IDH1 and IDH2 mutations have been associated with central nervous system tumors (gliomas) that respond poorly to therapy. The genes encode NADP+-dependent isocitrate dehydrogenases, enzymes that convert iso-citrate to a-ketoglutarate. The mutant enzymes gain ability to produce 2-hydroxyglutarate (2HG) which accumulates to high levels in the cells.

Metabolomic profiling discovered altered levels of amino acids, lipid pre-cursors and TCA intermediates in HOG cells expressing the mutant IDH genes and the altered metabolite levels were similar to those observed when the cells were treated with 2HG. The authors propose that deregulation of the TCA cycle and disrupted electron transport provide building blocks that lead to cell proliferation at the expense of nutrient production.

Dramatically reduced levels of the most common brain dipeptide, N-acetyl-aspartyl-glutamate (NAAG), were observed in the cells. NAAG levels were also significantly lower in human gliomas containing the IDH mutations than those without. While the contribution of NAAG to pathogenesis is unclear, it may provide a therapeutic target and its role merits further investigation.

The study showed that metabolomics analysis provided mechanistic insight into metabolic alterations in tumor cells that will be useful to design therapies targeted to cancer cell metabolism without harming non-cancer tissue.