Abstract
Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of reduced glutathione and peroxiredoxin, and produce α-ketoglutarate, a co-factor of numerous enzymes. IDH1/2 is mutated in ~70–80% of lower-grade gliomas and the majority of secondary glioblastomas. The mutant IDH1 (R132H), in addition to losing its normal catalytic activity, gains the function of producing the d-(R)-2-hydroxyglutarate (2-HG). Overproduction of 2-HG in cancer cells interferes with cellular metabolism and inhibits histone and DNA demethylases, which results in histone and DNA hypermethylation and the blockade of cellular differentiation. We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated with mutated IDH1/2, and their impact on tumor microenvironment and antitumor immunity. Isoform-selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings. Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas. We describe the development of small-molecule compounds and peptide vaccines targeting IDH-mutant gliomas and the results of their testing in preclinical and clinical studies. All those results support the translational potential of strategies targeting gliomas carrying IDH1 mutations.
Highlights
Functions of Isocitrate DehydrogenasesSince the initial discovery of mutations in the isocitrate dehydrogenase 1 (IDH1) gene by whole-genome sequencing in a large subset of human gliomas [1], and in acute myelogenous leukemia (AML) [2], much interest was focused on understanding consequences of mutations in Isocitrate dehydrogenases (IDH) genes and their roles in tumor progression
Introduction of mutantisocitrate dehydrogenase 1 (IDH1) or treatment with 2-HG reduced levels of a chemokine CXCL (C-X-C motif) 10, which was associated with decreased expression of a transcription factor STAT1, an inducer of inflammation
Depending on associated genomic aberrations and a cellular context, the oncogenic potential of IDH1/2 mutations ranges from an initiating event, which promotes transformation, to a secondary oncogenic event conferring selective advantage to cancer cells
Summary
Since the initial discovery of mutations in the isocitrate dehydrogenase 1 (IDH1) gene by whole-genome sequencing in a large subset of human gliomas [1], and in acute myelogenous leukemia (AML) [2], much interest was focused on understanding consequences of mutations in IDH genes and their roles in tumor progression. Isocitrate dehydrogenases 1 and 2 are key Krebs cycle enzymes that are nicotinamide adenine dinucleotide phosphate (NADP+ )-dependent and catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH1/2 proteins catalyze the oxidative decarboxylation of isocitrate to α-KG to produce reduced nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+. IDH1 and IDH2 enzymes maintain an adequate pool of reduced glutathione (GSH) and peroxiredoxin by providing NADPH. This maintains redox balance, protecting the cell against oxidative damage from various cellular stressors. NADPH generated by IDH1 is involved in lipid metabolism [6] and contributes to the cellular defense against reactive oxygen species (ROS) induced during lipid oxidation [7]. IDH1 and IDH2 are involved in glutamine metabolism under hypoxia and electron transport chain alterations [11]
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