Isocitrate Dehydrogenase 1

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 10224 Experts worldwide ranked by ideXlab platform

Hai Yan - One of the best experts on this subject based on the ideXlab platform.

  • biological role and therapeutic potential of idh mutations in cancer
    Cancer Cell, 2018
    Co-Authors: Matthew S Waitkus, Bill H Diplas, Hai Yan
    Abstract:

    Hotspot mutations in Isocitrate Dehydrogenase 1 (IDH1) and Isocitrate Dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.

  • cancer associated Isocitrate Dehydrogenase 1 idh1 r132h mutation and d 2 hydroxyglutarate stimulate glutamine metabolism under hypoxia
    Journal of Biological Chemistry, 2014
    Co-Authors: Zachary J Reitman, Ivan Spasojevic, Christopher G Duncan, Ethan Poteet, Ali Winters, Liangjun Yan, David M Gooden, Laszlo G Boros, Shaohua Yang, Hai Yan
    Abstract:

    Mutations in the cytosolic NADP(+)-dependent Isocitrate Dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers.

  • Isocitrate Dehydrogenase 1 what it means to the neurosurgeon a review
    Journal of Neurosurgery, 2013
    Co-Authors: Tiffany R Hodges, Darell D Bigner, Hai Yan, Bryan D Choi, John H Sampson
    Abstract:

    Isocitrate Dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.

  • profiling the effects of Isocitrate Dehydrogenase 1 and 2 mutations on the cellular metabolome
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Zachary J Reitman, Genglin Jin, Ivan Spasojevic, Jian Yang, Darell D Bigner, Edward D Karoly, Kenneth W Kinzler, Bert Vogelstein, Hai Yan
    Abstract:

    Point mutations of the NADP+-dependent Isocitrate Dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.

  • Isocitrate Dehydrogenase 1 and 2 mutations in cancer alterations at a crossroads of cellular metabolism
    Journal of the National Cancer Institute, 2010
    Co-Authors: Zachary J Reitman, Hai Yan
    Abstract:

    Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent Isocitrate Dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

Zachary J Reitman - One of the best experts on this subject based on the ideXlab platform.

  • cancer associated Isocitrate Dehydrogenase 1 idh1 r132h mutation and d 2 hydroxyglutarate stimulate glutamine metabolism under hypoxia
    Journal of Biological Chemistry, 2014
    Co-Authors: Zachary J Reitman, Ivan Spasojevic, Christopher G Duncan, Ethan Poteet, Ali Winters, Liangjun Yan, David M Gooden, Laszlo G Boros, Shaohua Yang, Hai Yan
    Abstract:

    Mutations in the cytosolic NADP(+)-dependent Isocitrate Dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers.

  • profiling the effects of Isocitrate Dehydrogenase 1 and 2 mutations on the cellular metabolome
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Zachary J Reitman, Genglin Jin, Ivan Spasojevic, Jian Yang, Darell D Bigner, Edward D Karoly, Kenneth W Kinzler, Bert Vogelstein, Hai Yan
    Abstract:

    Point mutations of the NADP+-dependent Isocitrate Dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.

  • Isocitrate Dehydrogenase 1 and 2 mutations in cancer alterations at a crossroads of cellular metabolism
    Journal of the National Cancer Institute, 2010
    Co-Authors: Zachary J Reitman
    Abstract:

    +-dependent Isocitrate Dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2–4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of d-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

  • Isocitrate Dehydrogenase 1 and 2 mutations in cancer alterations at a crossroads of cellular metabolism
    Journal of the National Cancer Institute, 2010
    Co-Authors: Zachary J Reitman, Hai Yan
    Abstract:

    Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent Isocitrate Dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

Timothy F Cloughesy - One of the best experts on this subject based on the ideXlab platform.

  • vorasidenib vor ag 881 an inhibitor of mutant idh1 and idh2 in patients pts with recurrent progressive glioma updated results from the phase i non enhancing glioma population
    Journal of Clinical Oncology, 2020
    Co-Authors: Ingo K Mellinghoff, Timothy F Cloughesy, Elizabeth A Maher, Macarena I De La Fuente, Gregory M Cote, Howard A Burris, Filip Janku, Katherine B Peters, Jennifer Leigh Clarke, Li Liu
    Abstract:

    2504Background: Isocitrate Dehydrogenase 1 and 2 mutations (mIDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D...

  • a phase i open label perioperative study of ag 120 and ag 881 in recurrent idh1 mutant low grade glioma results from cohort 1
    Journal of Clinical Oncology, 2019
    Co-Authors: Ingo K Mellinghoff, Benjamin M Ellingson, Timothy F Cloughesy, Elizabeth A Maher, Katherine B Peters, Patrick Y Wen, Jennie Taylor, Isabel Arrillaga, Changho Choi, Alexander P Lin
    Abstract:

    2003Background: AG-120 (ivosidenib [IVO]) is a first-in-class oral inhibitor of mutant Isocitrate Dehydrogenase 1 (mIDH1) evaluated in 66 glioma patients (pts) in an ongoing phase 1 study. AG-881 (...

  • phase 1 study of ag 881 an inhibitor of mutant idh1 idh2 in patients with advanced idh mutant solid tumors including glioma
    Journal of Clinical Oncology, 2018
    Co-Authors: Ingo K Mellinghoff, Timothy F Cloughesy, Elizabeth A Maher, Macarena I De La Fuente, Gregory M Cote, Howard A Burris, Filip Janku, Katherine B Peters, Marta Penasprado, Jennifer Clarke
    Abstract:

    2002Background: Isocitrate Dehydrogenase 1 and 2 mutations (mIDH1/2) occur in solid tumors including glioma, and result in production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting tumo...

  • d 2 hydroxyglutarate is necessary and sufficient for Isocitrate Dehydrogenase 1 mutant induced mir148a promoter methylation
    Molecular Cancer Research, 2018
    Co-Authors: Christopher D Cox, Linda M Liau, Byram Ozer, Nhung T Nguyen, Huytram N Nguyen, Thomas J Lai, Fei Liu, Harley I Kornblum, Phioanh L Nghiemphu, Timothy F Cloughesy
    Abstract:

    Mutant Isocitrate Dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG-dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP) and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated. In this study, we demonstrate that treatment with exogenous D-2-HG induces MIR148A promoter methylation and transcriptional silencing in human embryonic kidney 293T (293T) cells and primary normal human astrocytes. Conversely, we show that the development of MIR148A promoter methylation in mutant IDH1-overexpressing 293T cells is abrogated via treatment with C227, an inhibitor of mutant IDH1 generation of D-2-HG. Using dot blot assays for global assessment of 5-hydroxymethylcytosine (5-hmC), we show that D-2-HG treatment reduces 5-hmC levels, whereas C227 treatment increases 5-hmC levels, strongly suggesting TET inhibition by D-2-HG. Moreover, we show that withdrawal of D-2-HG treatment reverses methylation with an associated increase in MIR148A transcript levels and transient generation of 5-hmC. We also demonstrate that RNA polymerase II binds endogenously to the predicted promoter region of MIR148A, validating the hypothesis that its transcription is driven by an independent promoter.Implications: Establishment of D-2-HG as a necessary and sufficient intermediate by which mutant IDH1 induces CpG island methylation of MIR148A will help with understanding the efficacy of selective mutant IDH1 inhibitors in the clinic. Mol Cancer Res; 16(6); 947-60. ©2018 AACR.

  • detection of 2 hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in u87 glioma cells overexpressing Isocitrate Dehydrogenase 1 mutation
    Neuro-oncology, 2012
    Co-Authors: Jelena Lazovic, David Piccioni, Horacio Soto, Jerry R Lou, Leili Mirsadraei, William H Yong, Robert M Prins, Linda M Liau, Benjamin M Ellingson, Timothy F Cloughesy
    Abstract:

    The arginine 132 (R132) mutation of Isocitrate Dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.

Macarena I De La Fuente - One of the best experts on this subject based on the ideXlab platform.

Courtney D Dinardo - One of the best experts on this subject based on the ideXlab platform.

  • mutant Isocitrate Dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia
    Journal of Clinical Oncology, 2021
    Co-Authors: Courtney D Dinardo, Anthony S Stein, Eytan M Stein, Amir T Fathi, Olga Frankfurt, Andre C Schuh, Hartmut Dohner, Giovanni Martinelli, Prapti A Patel, Emmanuel Raffoux
    Abstract:

    PURPOSEIvosidenib is an oral inhibitor of the mutant Isocitrate Dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested...

  • Mutant Isocitrate Dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia
    'American Society of Clinical Oncology (ASCO)', 2020
    Co-Authors: Martinelli G, Courtney D Dinardo, As Stein, Daigle S, Choe S, Frankfurt O, Hm Kantarjian, Döhner H, Em Stein, At Fathi
    Abstract:

    PURPOSE: Ivosidenib is an oral inhibitor of the mutant Isocitrate Dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS: This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed mIDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922). RESULTS: Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). mIDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION: Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving mIDH1 mutation clearance.

  • ivosidenib ivo ag 120 in mutant idh1 relapsed refractory acute myeloid leukemia r r aml results of a phase 1 study
    Journal of Clinical Oncology, 2018
    Co-Authors: Daniel A Pollyea, Courtney D Dinardo, Eytan M Stein, Stephane De Botton, Gail J Roboz, Alice S Mims, Ronan T Swords, Jessica K Altman, Robert H Collins, Gabriel N Mannis
    Abstract:

    7000Background: IVO is an oral, targeted inhibitor of mutant Isocitrate Dehydrogenase 1 (mIDH1) that is being evaluated in a phase 1 dose escalation and expansion study of mIDH1 advanced hematologi...

Related terms

Isocitrate Dehydrogenase 1 - 15 days free trial to Access Experts & Abstracts