D-2-Hydroxyglutarate in Glioma Biology.
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ABSTRACT:
SUBMITTER: Chou FJ
PROVIDER: S-EPMC8464856 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
D-2-Hydroxyglutarate in Glioma Biology.
Chou Fu-Ju FJ Liu Yang Y Lang Fengchao F Yang Chunzhang C
Cells 20210907 9
Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in glioma, which result in the accumulation of an "oncometabolite", D-2-hydroxyglutarate (D-2-HG). Abnormally elevated D-2-HG levels result in a distinctive pattern in cancer biology, through competitively inhibiting α-ketoglutarate (α-KG)/Fe(II)-dependent dioxgenases (α-KGDDs). Recent studies have revealed that D-2-HG affects DNA/histone methylation, hypoxia signaling, DNA repair, and redox homeostasis, which impacts the ...[more]
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Project description:BackgroundRecurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated.MethodsIn this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort.ResultsWe found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type.ConclusionOur finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management.Implications for practicePatients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.
| S-EPMC4746092 | biostudies-literature
Project description:IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.
| S-EPMC6219629 | biostudies-literature
Project description:Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma-bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma-bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8+ T cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.
| S-EPMC7880418 | biostudies-literature
Project description:BackgroundMutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS.MethodsForty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas.ResultsA metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma.ConclusionsIDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.
| S-EPMC5063515 | biostudies-literature
Project description:Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes occur frequently in diffuse astrocytoma and oligodendroglioma. The consecutive amino acid substitutions in the mutant proteins result in a gain of the function to catalyze the reduction of alpha-ketoglutarate to 2-hydroxyglutarate (2HG). So far, all investigated IDH mutations share this gain of function. We here describe a method to detect 2HG levels in archival formalin-fixed paraffin-embedded tumor specimens by stable isotope dilution using gas chromatography followed by mass spectrometry (GC/MS). While 2HG levels are notably decreased during the routine embedding process, preserved amounts are still sufficient to indicate a mutation. Detection of 2HG in archival specimens could make routinely processed tissue accessible for research on 2HG accumulation and may allow studies on correlation with clinical data.
| S-EPMC8028858 | biostudies-literature
Project description:PurposeMeasurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy.Experimental designWe report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS).ResultsWe found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%;P= 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R(2)= 0.88,P= 0.002) with clinical status evaluated by KPS.ConclusionsWe demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas.
| S-EPMC4818725 | biostudies-literature
Project description:Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment.
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Project description:Integrins are a large family of transmembrane adhesion receptors, which play a key role in interactions of a cell with the surrounding stroma. Integrins are comprised of non-covalently linked ? and ? chains, which form heterodimeric receptor complexes. The signals from integrin receptors are combined with those originating from growth factor receptors and participate in orchestrating morphological changes of cells, organization of the cytoskeleton, stimulation of cell proliferation and rescuing cells from programmed cell death induced by extracellular matrix (ECM) detachment. Upon binding to specific ligands or ECM components, integrin dimers activate downstream signaling pathways, including focal adhesion kinase, phosphoinositide-3-kinase (PI3K) and AKT kinases, which regulate migration, invasion, proliferation and survival. Expression of specific integrins is upregulated in both tumor cells and stromal cells in a tumor microenvironment. Therefore, integrins became an attractive therapeutic target for many cancers, including the most common primary brain tumors-gliomas. In this review we provide an overview of the involvement of integrin signaling in glioma pathogenesis, formation of the tumor niche and brain tissue infiltration. We will summarize up-to-date therapeutic strategies for gliomas focused on interference with integrin ligand-receptor signaling.
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Project description:BackgroundGliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both.Methodology/principal findingsWe show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein).ConclusionsBinding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis.
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Project description:Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.
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