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See detailIdentifying and targeting metabolic vulnerabilities of IDH mutant gliomas
Cano Galiano, Andrés UL

Doctoral thesis (2021)

Diffuse gliomas are a group of central nervous system (CNS) tumors with a poor patient prognosis. Within these diffuse gliomas, isocitrate dehydrogenase (IDH) mutation defines the different tumor subtypes ... [more ▼]

Diffuse gliomas are a group of central nervous system (CNS) tumors with a poor patient prognosis. Within these diffuse gliomas, isocitrate dehydrogenase (IDH) mutation defines the different tumor subtypes and is considered to be an initiating event in gliomagenesis. IDH is a metabolic enzyme that in normal conditions mediates the conversion of isocitrate into α-ketoglutarate (α-KG), producing the reducing equivalent NADPH. IDH mutation (IDHm) leads to a neomorphic reaction where α-KG is consumed to generate the oncometabolite D-2-hydroxyglutarate (D-2HG), using NADPH as reducing agent. It has been reported that IDHm-dependent D-2HG synthesis has a direct impact on DNA and histone methylation, however the metabolic repercussions are not yet well defined. Due to the consumption of NADPH by IDHm reaction, some groups including us have hypothesized that IDHm cells may bear an imbalance of reducing equivalents, that may trigger a defective antioxidant defense. In the present study we made use of patient-derived cell lines and xenografts thereof as well as clinical samples in order to study the metabolic vulnerabilities of IDHm gliomas. In the first part of the thesis experimental data, we generated an integrative liquid chromatography-mass spectrometry (LCMS)-based proteomic-metabolomic characterization of IDHm metabolism. We made use of patients, cell lines and xenografts to address the direct effect of the mutation. We observed that IDHm gliomas have altered regulation of key processes in central carbon metabolism through glucose and glutamate processing as well as glutathione (GSH) metabolism and fatty acid production. In the second part of experimental data, we investigated the redox vulnerabilities of IDHm gliomas. Here we discovered that IDHm astrocytomas specifically upregulate cystathionine-γ-lyase (CSE) enabling them to synthesize GSH independently of NADPH. CSE is the only known enzyme capable of synthesizing cysteine. We found that genetic and chemical inhibition of CSE led to a decrease in cell viability upon cysteine restriction. Finally inhibition of CSE in vivo led to a delay in tumor growth rate. In conclusion, in the present PhD dissertation we expose a comprehensive study of the metabolic behavior of IDHm human gliomas, and we propose a novel therapeutic strategy that might improve patient prognosis, by inflicting oxidative damage to the tumor. [less ▲]

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