Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

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.

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

“…Isocitrate dehydrogenases 1 and 2 (IDH1, and IDH2) are key TCA cycle enzymes that are nicotinamide adenine dinucleotide phosphate (NADP + ) dependent. IDH1 and 2 catalyze the oxidative decarboxylation of isocitrate to α-KG with production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) (180). Mutations in IDH1 and IDH2 genes are mostly missense variants leading to a single amino-acid substitution of arginine residues at codon 132 in exon 4 of the IDH gene or codons 140 or 172 of the IDH2 gene.…”

“…Mutations in IDH1 and IDH2 genes are mostly missense variants leading to a single amino-acid substitution of arginine residues at codon 132 in exon 4 of the IDH gene or codons 140 or 172 of the IDH2 gene. Mutant of IDH1 and IDH2 enzymes have a gain the function of catalyzing the reduction of α-KG to its (R)-enantiomer of 2-hydroxyglutarate (2HG), which accumulates to exceedingly high levels in patients with glioma, acute myeloid leukemia, esophageal squamous cell carcinoma (180)(181)(182)(183) thus, 2HG levels being used as a biomarker for IDH mutation in these cancers (184). 2HG is an oncometabolite impairing epigenetic and hypoxic regulation through its binding to α-KG-dependent dioxygenases.…”

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

“…Some cancers, such as glioblastoma, chondrosarcoma, leukemia and colorectal cancer, have mutations in isocitrate dehydrogenase 1/2 (IDH1/2) [13,[39][40][41]. Mutant IDH1/2 uses NADPH to convert α-ketoglutarate (α-KG) into D-2HG, an oncometabolite that causes hypermethylation at…”

“…CpG islands or loss of exon 1 expression in NAPRT [7][8][9]39,40]. As a consequence, inhibition of NAPRT enzyme activity forces these cells to mainly depend on the NAD salvage pathway to generate NAD ( Figure 1) [7].…”

“…Demonstrating the effect of restricting the NAD pool in halting cancer progression requires the inhibition of vital pathways, and the reduction of redundancy [38]. This may be achieved in cancer cells that are deficient in one of the NAD biogenesis pathways.Some cancers, such as glioblastoma, chondrosarcoma, leukemia and colorectal cancer, have mutations in isocitrate dehydrogenase 1/2 (IDH1/2) [13,[39][40][41]. Mutant IDH1/2 uses NADPH to convert α-ketoglutarate (α-KG) into D-2HG, an oncometabolite that causes hypermethylation at…”