Abstract 431: IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis

Abstract

Abstract Hotspot mutations in isocitrate dehydrogenase 1 (IDH1MT) initiate low grade glioma (LGG) and secondary glioblastoma and induce neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). This causes metabolic rewiring that is not fully understood and in vitro studies have shown that IDH1MT cancer cells rely on glutaminolysis, providing cells with α-KG via activities of glutaminase (GLS) and glutamate dehydrogenase (GLUD). Here, we first show by in silico analysis of 269 IDH1 wild-type (IDH1WT) and 408 IDH1MT gliomas, obtained from the The Cancer Genome Atlas (TCGA) database, that IDH1WT gliomas have high expression levels of genes encoding for enzymes that are involved in glycolysis and acetate anaplerosis. On the other hand, the tricarboxylic acid (TCA) cycle, rather than glycolytic lactate production, is the predominant metabolic pathway in IDH1MT gliomas and is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. IDH1WT- and IDH1MT-related differences in expression were found in both LGG and glioblastoma. Furthermore, via in situ enzymatic activity mapping, we show in human gliomas and in xenocraft models that GLUD activity is increased and GLS activity is decreased in IDH1MT glioma, indicating that IDH1MT gliomas depend on glutamatolysis, rather than glutaminolysis. We show that transcript levels in our xenocraft models are in good agreement with our in silico analysis of the TCGA database. Finally, we confirmed the glutamate dependency of IDH1MT gliomas by MRS-flux analysis, whereas IDH1WT gliomas show high lactate production. Taken together, we show that IDH1WT gliomas have a typical Warburg phenotype and rely on acetate anaplerosis whereas IDH1MT gliomas are glutamate and lactate dependent. This metabolic rewiring in IDH1MT glioma, enables targeting of glutaminolysis rather than direct inhibition of IDH1MT for therapy. It diminishes the supply of glutamate-derived α-KG and directly inhibits the production of D-2-HG and simultaneously worsen the redox status of the glioma cells by inhibiting NAD(P)H production by GLUD. A candidate drug to inhibit GLUD is epigallocatechin-3-gallate gallate, a component of green tea that is currently receiving high interest as anti-cancer agent. Note: This abstract was not presented at the meeting. Citation Format: Mohammed Khurshed, Krissie Lenting, Remco J. Molenaar, William P. Leenders, Cornelis J. van Noorden. IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2017-431