Isocitrate dehydrogenase‐mutant glioma: Evolving clinical and therapeutic implications

Miller, Julie J.; Shih, Helen A.; Andronesi, Ovidiu C.; Cahill, Daniel P.

doi:10.1002/cncr.31039

Cited by 116 publications

(85 citation statements)

References 93 publications

(224 reference statements)

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“…The TCA cycle has been implicated as a potential therapeutic target in IDH1-mutant gliomas [30] and our observation that the TCA cycle is compromised in IDH1 R132H cells supports this possibility. Altered metabolism in IDH1-mutant tumors can also be used for diagnostic purposes: high levels of 2-HG or decreased levels of glutamate can be detected using in vivo magnetic resonance spectroscopy (MRS) [31,32].…”

Section: Discussionmentioning

confidence: 99%

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Biedermann

Preussler

Conde

et al. 2019

Cancers

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IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.

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Section: Discussionmentioning

confidence: 99%

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Biedermann

Preussler

Conde

et al. 2019

Cancers

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“…Different groups quickly moved away from broad genetic analyses to the characterization of imaging phenotypes for specific mutations in GBM. Isocitrate dehydrogenase-1 (IDH) mutation is commonly used in the clinic to stratify patients, often in conjunction with other co-mutations [49] and it received the most attention in brain radiogenomic research. IDH-mutated gliomas occurred most frequently in the rostral extension of the lateral ventricles of the frontal lobe [50] and were linked to tumor size [51], local pattern of intensities [52], PET features [53,54], angular standard deviation (tumor boundary irregularity) [41], mean diffusional kurtosis [55], and apparent diffusion coefficient (ADC) [56] as well as part of "radiomic signatures" in artificial intelligence models [20,[57][58][59][60][61][62].…”

Section: Brainmentioning

confidence: 99%

Radiogenomics: bridging imaging and genomics

et al. 2019

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From diagnostics to prognosis to response prediction, new applications for radiomics are rapidly being developed. One of the fastest evolving branches involves linking imaging phenotypes to the tumor genetic profile, a field commonly referred to as "radiogenomics." In this review, a general outline of radiogenomic literature concerning prominent mutations across different tumor sites will be provided. The field of radiogenomics originates from image processing techniques developed decades ago; however, many technical and clinical challenges still need to be addressed. Nevertheless, increasingly accurate and robust radiogenomic models are being presented and the future appears to be bright.

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“…IDH1/2 mutations should arise during embryonic development due to the somatic mosaic of mutant IDH1/ 2-expressing cells, such as IDH1 R132H/C/L/S or R100Q and IDH2 R140Q/G/W/L or R172K/G/M/Q/T/S, which are common mutations in gliomas (bold are the most frequent) (20,180). This is accompanied by loss-of-function mutations of the p53 protein (110). A specific human isoform of glutamate dehydrogenase 2 (GDH2) was also reported to promote glioma.…”

Section: Hg As An Oncometabolitementioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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Isocitrate dehydrogenase‐mutant glioma: Evolving clinical and therapeutic implications

Cited by 116 publications

References 93 publications

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Radiogenomics: bridging imaging and genomics

2-Hydroxyglutarate in Cancer Cells

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