Recently, cancer genome sequencing projects identified recurrent mutations in the isocitrate dehydrogenases (IDH) within both low grade and high grade gliomas. Gliomas with these gain- of-function isocitrate dehydrogenase mutations produce millimolar amounts of the metabolite D- 2 hydroxyglutarate consuming alpha-ketoglutarate and NADPH in the process. D-2HG, which has been called an oncometabolite, can reversibly transform cells in vitro at high concentrations, and hence is important for both tumor initiation and maintenance. Paradoxically, in some cancers IDH1 mutant tumors actually have a better prognosis than wildtype tumors of matching grade. A contributing factor has been hypothesized to be a metabolic state not optimal for proliferation caused by the production of D-2HG. An important question is whether or not gliomas have metabolic adaptations to support the accumulation of D-2 hydroxyglutarate, and whether adaptations to D-2 hydroxyglutarate production would provide novel therapeutic targets for this progressive disease. The following fellowship proposal is aimed at characterizing metabolic adaptations to IDH1 mutation using patient derived cell lines with endogenous IDH1 mutations and isogenic patient derived lines with the endogenous IDH1 mutation knocked out via Cas9 gene editing. Expression data from low grade gliomas with and without IDH1 mutations available in public databases will be used to identify putatively differentially expressed target genes, whose IDH1 mutation status dependent expression will be tested using the isogenic pairs as well as octyl-D2HG. The overall goal is to identify alterations in metabolism that support the growth of IDH1 mutant tumors and hence may be interesting targets for therapy.
World Health Organization grade II and grade III gliomas are central nervous system cancers which almost invariably progress to higher grade life-threating tumors. The majority of these gliomas contain recurrent mutations within the isocitrate dehydrogenase 1 gene, which is responsible for altering their cell metabolism. Some of these alterations may support the growth of the gliomas with isocitrate dehydrogenase mutations, and thus preventing or interfering with the altered metabolism could be a therapeutic paradigm within these cancers. This proposal aims to investigate whether cells adapt their metabolism in response to the recurrent isocitrate dehydrogenase 1 mutations, and aims to provide a rational means of interfering with the altered metabolic state within these tumors.
