Cancer Metabolism Breakthrough: IDH1 Mutations Linked to Brain Cancer

Scientists at Agios Pharmaceuticals have made a groundbreaking discovery in the field of cancer metabolism, establishing that the mutated IDH1 gene has a novel enzyme activity consistent with a cancer-causing gene, or oncogene. This breakthrough reveals that the mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of gliomas, the most common type of brain cancer.

Key Takeaways:

• The mutated IDH1 gene has a novel enzyme activity consistent with a cancer-causing gene, or oncogene, producing a metabolite, 2-hydroxyglutarate (2HG).
• This discovery shows that IDH1 mutations are linked to gliomas, the most common type of brain cancer, with approximately 70% of gliomas having the IDH1 mutation.
• Analysis of tumor samples of brain cancer patients with the IDH1 mutation revealed up to hundred-fold elevations in concentrations of 2HG, a metabolite previously linked to brain cancer formation.
• The research team employed novel techniques in cancer metabolism to study the IDH1 mutation, including large-scale profiling of hundreds of cellular metabolites, x-ray crystallography, and innovative enzymology.
• The discovery provides a new understanding of the role of IDH1 in cancer and opens potential for new class of cancer drugs targeting IDH1 metabolic enzymes.
• The biomarker, 2HG, could be used to develop an important diagnostic tool for gliomas and potentially other cancers with IDH1 mutations.
• The research was published on November 22 by the journal Nature, in a paper entitled "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2HG)".

Statistics:

• 70% of gliomas are known to have the IDH1 mutation (Source: Nature, 2008).
• Up to hundred-fold elevations in concentrations of 2HG were found in tumor samples of brain cancer patients with the IDH1 mutation (Source: Agios Pharmaceuticals).
• 20,000 Americans are affected by gliomas each year (Source: American Cancer Society).
• More than half of glioma patients die within 18 months of diagnosis (Source: American Cancer Society).

Sources:

• [1] Dang et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;In press. DOI: 10.1038/nature08617
• [2] Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-12 (2008); Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360, 765-73 (2009)