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Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α -ketoglutarate (α -KG). Mutants of IDH1 or IDH2 can produce d -2-hydroxyglutarate (D-2HG) with α -KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2 , implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers. Isocitrate dehydrogenase 1 (IDH1) is a potential target for cancer treatment. Mutant IDH1 promotes the occurrence and development of cancer by influencing metabolism, immune microenvironment, epigenetics, and phenotype. [Display omitted] [ABSTRACT FROM AUTHOR]

IDH1 is a key metabolic enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle that can convert isocitrate into α-ketoglutarate (α-KG) and generate NADPH. The reduction of IDH1 may affect dioxygenase activity and damage the body's detoxification mechanism. Many studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 expression levels or gene mutations have appeared in many tumor tissues and produced a series of metabolic and immunity changes at the same time. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors. IDH1 is a key metabolic enzyme for cellular respiration. The changes in IDH1 expression or gene mutations may affect enzyme activity and damage the body's detoxification mechanism. Studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 also produced a series of metabolic and immunity changes. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors. [ABSTRACT FROM AUTHOR]

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

Isocitrate dehydrogenases (IDHs) are metabolic enzymes that are mutated in several cancers, resulting in overproduction of d‐2‐hydroxyglutarate (D‐2HG). However, the signalling pathways and factors that regulate mutant IDHs or their metabolites remain elusive. Here, we report that in synchronized cells and cells treated with anti‐mitotic agents, wild‐type and mutant IDH proteins are induced maximally in G2/M. Moreover, mutant IDH1‐expressing cells arrested in G2/M harbour high D2HG levels. Genetic or pharmacological perturbation of Forkhead box protein M1 (FOXM1) abrogates the levels of IDH1 mRNA, protein and D2HG in G2/M. Conversely, overexpression of FOXM1 or hyperactive FOXM1 activates the IDH1 promoter and increases the abundance of its protein levels. In summary, our results show that in G2/M, higher D2HG levels are dependent on FOXM1‐mediated transcription of IDH1. [ABSTRACT FROM AUTHOR]

Mutations in the metabolic enzymes, IDH1 and IDH2 are frequently found in glioma, chondrosarcoma, and acute myeloid leukemia. In our previous study, we showed that mutant IDH1 and IDH2 proteins levels are high in mitosis, and mutant IDH1 enzyme activity increases in mitosis. In another study, we observed that mutant IDH2 is ubiquitinated in mitosis in an APC/C-dependent manner. To orchestrate mitosis, kinases phosphorylate key proteins and regulate their functions. But it is unknown, whether mitotic kinases regulate mutant IDH1 and IDH2. As IDH1 and IDH2 have 66% sequence identity, thus we hypothesized that a common mitotic kinase(s) may regulate mutant IDH1 and IDH2 in mitosis. To test our hypothesis, we examined mutant IDH1 and IDH2 binding to mitotic kinases and determined their role in regulating mutant IDH1 and IDH2 in mitosis. Here, we observed that Cdk1/Cyclin B1 phosphorylated mutant IDH1 and IDH2 binds Plk1. Conserved Plk1 phosphobinding sites in IDH1 and IDH2 are important for Plk1 binding. We found that Plk1 regulates mutant IDH1 enzyme activity and blocking Plk1 decreases D-2HG, whereas, overexpressing Plk1 increases D-2HG levels. Furthermore, blocking Plk1 decreases mutant IDH2 ubiquitination, whereas, overexpressing Plk1 increases mutant IDH2 ubiquitination in mitosis. We conclude that Plk1 regulates mutant IDH1 enzyme activity and mutant IDH2 ubiquitination in mitosis. Based on our results, we suggest that Plk1 can be a therapeutic target in mutant IDH-linked tumours. Proposed molecular mechanism of Plk1 regulating mutant IDH1 enzyme activity and mutant IDH2 ubiquitination. [Display omitted] • Cdk1 and Plk1 bind mutant IDH1 and IDH2 proteins. • Overexpressing Plk1 increases mutant IDH1 enzyme activity. • Modulating Plk1 affects mutant IDH2 ubiquitination. [ABSTRACT FROM AUTHOR]

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments. • H3.3K27M mutations enhance glucose, glutamine, and TCA cycle metabolism • TCA cycle intermediate α-KG enables maintenance of H3K27 hypomethylation • Targeting enzymes related to α-KG synthesis including WT-IDH1 and/or GDH is therapeutic • H3.3K27M and mutant-IDH1 in gliomas are mutually exclusive and are synthetic lethal Chung et al. show that H3.3K27M mutation in DIPGs enhances glycolysis and TCA cycle metabolism to produce α-KG that is required to maintain a preferred epigenetic state of low H3K27me3. Inhibiting enzymes related to α-KG production increases H3K27me3 and results in anti-tumor activity in mouse models of DIPG. [ABSTRACT FROM AUTHOR]

We describe a liquid chromatography-tandem mass spectrometry assay for measurement of D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. These metabolites are increased in specific inborn errors of metabolism and are now recognized as oncometabolites. The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia.