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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.

  • isocitrate dehydrogenase mutations in gliomas mechanisms biomarkers and therapeutic target
    Current Opinion in Neurology, 2011
    Co-Authors: Changcun Guo, Christopher J Pirozzi, Giselle Y Lopez, Hai Yan
    Abstract:

    Purpose of reviewIsocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-

  • 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.

  • 2 hydroxyglutarate production but not dominant negative function is conferred by glioma derived nadp dependent isocitrate dehydrogenase mutations
    PLOS ONE, 2011
    Co-Authors: Genglin Jin, Zachary J Reitman, Ivan Spasojevic, Ines Batinichaberle, Jian Yang, Oleg Schmidtkittler, Darell D Bigner, Hai Yan
    Abstract:

    Background Gliomas 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 Findings We 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). Conclusions Binding 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.

  • 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.

Samuel V Agresta - One of the best experts on this subject based on the ideXlab platform.

Lipika Goyal - One of the best experts on this subject based on the ideXlab platform.

  • circulating oncometabolite 2 hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant intrahepatic cholangiocarcinoma
    Clinical Cancer Research, 2014
    Co-Authors: Darrell R Borger, Lipika Goyal, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Vikram Deshpande, Hua Yang, Hyeryun Kim
    Abstract:

    Purpose: Mutations in the IDH1 and IDH2 ( IDH1 / 2 ) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1 / 2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1 / 2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. Experimental Design: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1 / 2 mutational status, tumor burden, and a number of clinical variables. Results: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1 / 2 -mutant (median, 478 ng/mL) versus IDH1 / 2 –wild-type (median, 118 ng/mL) tumors ( P P IDH1 / 2 -mutant cases ( P IDH1 / 2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. Conclusions: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884–90. ©2014 AACR .

  • circulating oncometabolite 2 hydroxyglutarate 2hg as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant idhm intrahepatic cholangiocarcinoma icc
    Journal of Clinical Oncology, 2013
    Co-Authors: Lipika Goyal, Darrell R Borger, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Katharine E Yen, Kimberly Straley, Samuel V Agresta
    Abstract:

    4125 Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts [11 IDHm, 22 IDH wild-type (IDHwt)] of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml [interquartile range 174–643]) versus IDHwt ICC pts (118ng/ml [68–160])(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated...

  • circulating oncometabolite 2 hydroxyglutarate 2hg as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant idhm intrahepatic cholangiocarcinoma icc
    Journal of Clinical Oncology, 2013
    Co-Authors: Lipika Goyal, Darrell R Borger, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Katharine E Yen, Kimberly Straley, Samuel V Agresta
    Abstract:

    4125 Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG leve...

Keyur P Patel - One of the best experts on this subject based on the ideXlab platform.

  • leukemia stemness and co occurring mutations drive resistance to idh inhibitors in acute myeloid leukemia
    Nature Communications, 2021
    Co-Authors: Feng Wang, Keyur P Patel, Courtney D Dinardo, Kiyomi Morita, Ken Furudate, Tomoyuki Tanaka, Yuanqing Yan, Kyle J Macbeth, Guowen Liu
    Abstract:

    Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.

  • leukemia stemness and co occurring mutations drive resistance to idh inhibitors in acute myeloid leukemia
    Nature Communications, 2021
    Co-Authors: Feng Wang, Keyur P Patel, Courtney D Dinardo, Kiyomi Morita, Ken Furudate, Tomoyuki Tanaka, Yuanqing Yan, Kyle J Macbeth, Guowen Liu
    Abstract:

    Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML. The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.

  • idh1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression
    Leukemia, 2016
    Co-Authors: Courtney D Dinardo, Keyur P Patel, Elias Jabbour, Koichi Takahashi, Naval Daver, Mark J Routbort, Mark Brandt, Sherry Pierce, Hagop M Kantarjian
    Abstract:

    Recurrent pathogenic mutations in IDH1 and IDH2 at the conserved amino acid sites IDH1-R132, IDH2-R140 and IDH2-R172 occur in ~20% of patients with acute myeloid leukemia (AML).1 A recent analysis of AML patients at our institution identified IDH1/2 mutations in 20% (n=167) of 826 AML patients, with IDH1/2 mutations occurring most frequently in the setting of diploid karyotype or other intermediate-risk cytogenetics, particularly trisomy 8 (77 vs 53%, P<0.0005). AML patients with IDH1/2 mutations were overall less likely to have a diagnosis of therapy-related AML (8 vs 17%, P=0.003).2

  • prognostic significance of alterations in idh enzyme isoforms in patients with aml treated with high dose cytarabine and idarubicin
    Cancer, 2012
    Co-Authors: Keyur P Patel, Rajyalakshmi Luthra, Mark Brandt, Sherry Pierce, Stefan Faderl, Marina Konopleva, Tapan M Kadia, Steven M Kornblau, Michael Andreeff
    Abstract:

    BACKGROUND: IDH1 and IDH2 gene mutations are novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML). METHODS: Among 358 patients with AML treated on 4 protocols using high-dose ara-C plus idarubicin induction, pretreatment samples were available for 170 (median age 53 years, [range, 17-73]; 96% ≤65) and were evaluated for IDH1R132, IDH2R172, and IDH2R140 mutations or the codon 105 single nucleotide polymorphism (SNP) in IDH1. RESULTS: IDH1 and IDH2 mutations were present in 12 (7%) and 24 (14%) of patients, and IDH1 G105 SNP in 24 (14%). Overall, 52 (30%) patients had IDH gene alterations. There was no association with complete response (CR), remission duration, overall survival, and event-free survival and any of the IDH alterations, and no association with a higher CR rate or survival with the 4 regimens for the 52 patients with aberrant IDH. Among the patients with diploid karyotype and NPM1mutFLT3WTgenotype, those with IDH1 or IDH2 mutations had an inferior outcome. CONCLUSIONS: IDH aberrations and IDH1 codon 105 SNP occur in about 30% of younger patients with AML, mostly with diploid karyotype. Using high-dose ara-C-based induction regimens, we did not detect an association with outcome for any of the aberrations. Cancer 2011;. © 2011 American Cancer Society.

  • diagnostic testing for idh1 and IDH2 variants in acute myeloid leukemia an algorithmic approach using high resolution melting curve analysis
    The Journal of Molecular Diagnostics, 2011
    Co-Authors: Keyur P Patel, Bedia A Barkoh, Jeffrey L Medeiros, Zhao Chen, Neelima Reddy, Rajyalakshmi Luthra
    Abstract:

    Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations and polymorphism are reported in 5% to 15% of acute myeloid leukemia (AML) cases, with G105 and R132 of IDH1 and R140 and R172 of IDH2 known to be clinically significant. Current Sanger sequencing assays to detect IDH mutations are labor intensive and not cost effective for clinical testing of low-frequency mutations. Therefore, we developed clinical assays using high-resolution melting (HRM) analysis to screen for all four variants listed above, followed by Sanger sequencing confirmation. The sensitivities of the assays were 7.3% and 7.9% for the detection of IDH2 and IDH1 variants, respectively, against the background of wild-type transcripts. Comparison of HRM to Sanger sequencing on 146 AML bone marrow samples for validation showed near-perfect concordance for all positive and negative results for IDH1 (98%) and IDH2 (94%). Postvalidation clinical implementation of upfront HRM screening (N = 106), using a more conservative algorithm to avoid false-negative results, reduced the number of Sanger sequencing tests by 73% (IDH1) and 78% (IDH2). Of the variant calls made by HRM in postvalidation clinical samples, Sanger confirmed the presence of a variant in 62% (IDH1) and 44% (IDH2) of the samples. In conclusion, our HRM assays are rapid, convenient, and versatile assays for screening and confirmation of alterations in IDH1 and IDH2.

Darrell R Borger - One of the best experts on this subject based on the ideXlab platform.

  • circulating oncometabolite 2 hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant intrahepatic cholangiocarcinoma
    Clinical Cancer Research, 2014
    Co-Authors: Darrell R Borger, Lipika Goyal, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Vikram Deshpande, Hua Yang, Hyeryun Kim
    Abstract:

    Purpose: Mutations in the IDH1 and IDH2 ( IDH1 / 2 ) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1 / 2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1 / 2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. Experimental Design: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1 / 2 mutational status, tumor burden, and a number of clinical variables. Results: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1 / 2 -mutant (median, 478 ng/mL) versus IDH1 / 2 –wild-type (median, 118 ng/mL) tumors ( P P IDH1 / 2 -mutant cases ( P IDH1 / 2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. Conclusions: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884–90. ©2014 AACR .

  • circulating oncometabolite 2 hydroxyglutarate 2hg as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant idhm intrahepatic cholangiocarcinoma icc
    Journal of Clinical Oncology, 2013
    Co-Authors: Lipika Goyal, Darrell R Borger, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Katharine E Yen, Kimberly Straley, Samuel V Agresta
    Abstract:

    4125 Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts [11 IDHm, 22 IDH wild-type (IDHwt)] of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml [interquartile range 174–643]) versus IDHwt ICC pts (118ng/ml [68–160])(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated...

  • circulating oncometabolite 2 hydroxyglutarate 2hg as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant idhm intrahepatic cholangiocarcinoma icc
    Journal of Clinical Oncology, 2013
    Co-Authors: Lipika Goyal, Darrell R Borger, Thomas Yau, Ronnie T P Poon, Marek Ancukiewicz, David C Christiani, Hannah M Liebman, Katharine E Yen, Kimberly Straley, Samuel V Agresta
    Abstract:

    4125 Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether serum 2HG leve...

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