The Significance of Isocitrate Dehydrogenase Mutations in Gliomas

The goal of this research proposal is to determine the mechanism(s) by which mutant isocitrate dehydrogenase 1 (IDH1) causes brain tumors to be less aggressive. The most common type of brain tumor is the diffusely infiltrative glioma; these tumors cannot be completely excised surgically, and are difficult to treat with radiation and chemotherapy. Thus, infiltrative gliomas are incurable. A specific point mutation in IDH1 (and a less common analogous mutation in IDH2) has been found to be quite frequent in these gliomas. When present, it is a powerful favorable prognostic factor, being strongly associated with longer patient survival. Mutant IDH1 has recently been shown to produce a novel compound, 2-hydroxyglutarate (2-HG). However, the effects of mutant IDH1 and 2-HG on glioma cells are unknown. Other work showed that 2-HG causes oxidative stress in nonneoplastic tissue models, and our preliminary data indicate that 2-HG is toxic to glioma cells and induces autophagy, ERK activation, and reactive oxygen species production. We therefore hypothesize that the improved survival imparted by mutant IDH1 in diffuse gliomas is due to 2-HG-induced production of reactive oxygen species, leading to oxidative damage and cell death. We also hypothesize that the cell death is primarily by autophagy, a form of programmed cell death involving lysosomes that has been shown to be prominent in many gliomas. To test these hypotheses, glioma cells will be treated with 2-HG or transfected with mutant IDH1, and multiple well-described markers of autophagy and reactive oxygen species will be measured. Response of glioma cells to autophagy and reactive oxygen species modulation will be assessed. For patient-derived tumor biopsies and human-mouse xenografts, immunohistochemical markers of autophagy and oxidative stress will be quantified and correlated with IDH mutation status. Success in this project would determine whether mutant IDH1 causes increased oxidative stress and autophagy in gliomas, thereby producing a less aggressive glioma compared to tumors that are wild type for IDH1. This knowledge could then be exploited to develop novel ways of treating gliomas.