METB-09IDENTIFYING NOVEL VULNERABILITIES IN OXIDATIVE STRESS PATHWAYS IN IDH1 MUTANT GLIOMA

Abstract

BACKGROUND: Glial tumors presenting a heterozygous point mutation in isocitrate dehydrogenase (IDH) accumulate the oncometabolite D-2-hydroxyglutarate (2-HG) leading to a hypermethylation phenotype through inhibition of α-ketoglutarate (α-KG) dependent demethylases. However the direct effect of the IDH mutation on metabolic dysregulation remains poorly understood. IDH mutant glioma cells are notoriously difficult to grow in vitro and only a handful of laboratories, including ours, have been able to generate patient derived xenograft models in vivo. Here we aimed to get insight into the major metabolic aberrations observed in human IDH mutant gliomas with a special emphasis on the energy metabolism, oxidative stress and glutamine/glutamate pathways. METHODS: In situ high resolution mass spectrometric imaging (MSI) was performed on IDH1 mutant xenograft sections derived from human oligodendroglial tumors with 1p19q deletion, providing a detailed metabolic profiling and anatomical localization in tumor sections. Key enzymes of the perturbed metabolic pathways were monitored by Western blot and immunohistochemistry. Liquid chromatography mass spectrometry (LC-MS) was applied to validate findings in clinical specimen. RESULTS: 2-HG was specifically localized in the tumor bed but not in the surrounding brain parenchyma, while α-KG levels were not significantly altered in IDH1 mutant tumors. We identified a large set of differential metabolites in IDH1-mutant tumors, including changes in lipid metabolism, in the methylation and the glutathione pathway. CONCLUSIONS: We provide a detailed metabolic mapping of human IDH mutant gliomas with high anatomical resolution in situ. Our data point to the importance of oxidative stress regulation and its possible link to epigenetic dysregulation in IDH mutant gliomas.