Volume 14 Issue 2
Mar.  2023
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LIN Meijia, ZENG Yeting, WANG Xinrui, HUANG Xiongfei. Research Progress of Isocitrate Dehydrogenase Gene Mutation Therapy[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(2): 346-352. doi: 10.12290/xhyxzz.2022-0176
Citation: LIN Meijia, ZENG Yeting, WANG Xinrui, HUANG Xiongfei. Research Progress of Isocitrate Dehydrogenase Gene Mutation Therapy[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(2): 346-352. doi: 10.12290/xhyxzz.2022-0176

Research Progress of Isocitrate Dehydrogenase Gene Mutation Therapy

doi: 10.12290/xhyxzz.2022-0176
Funds:

Natural Science Foundation of Fujian Province 2022J01662

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  • Corresponding author: HUANG Xiongfei, E-mail: 15705917895@163.com
  • Received Date: 2022-04-03
  • Accepted Date: 2022-09-07
  • Available Online: 2022-12-30
  • Publish Date: 2023-03-30
  • Isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, plays an important role in cellular energy metabolism. When the IDH gene is mutated, the enzyme activity is altered, resulting in an accumulation of a large amount of the tumor metabolite 2-hydroxyglutaric acid (2-HG), causing severe epigenetic deregulation and dysregulation of gene expression, and promoting tumorigenesis. Recent studies have shown that IDH1 and IDH2 mutations are closely related to the occurrence and development of a variety of tumors such as glioma, acute myeloid leukemia(AML) and intrahepatic cholangiocarcinoma(iCCA) as well as their clinical treatment. It is of great significance to use IDH gene mutations as molecular indicators for detecting glioma, AML and iCCA tumorigenesis, and developing targeted drugs. This review is focused on the mechanism of IDH mutation, the relationship between mutant IDH and the development of multiple tumors, and the progress of treatment of IDH mutation in basic research and drug clinical trials.
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  • [1] Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in glioma[J]. Neuro Oncol, 2016, 18: 16-26. doi:  10.1093/neuonc/nov136
    [2] Biaglow JE, Miller RA. The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy[J]. Cancer Biol Ther, 2005, 4: 6-13.
    [3] Aykin-Burns N, Ahmad IM, Zhu Y, et al. Increased levels of superoxide and H2O2 mediate the differential suscep-tibility of cancer cells versus normal cells to glucose deprivation[J]. Biochem J, 2009, 418: 29-37. doi:  10.1042/BJ20081258
    [4] Yang B, Zhong C, Peng Y, et al. Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H[J]. Cell Res, 2010, 20: 1188-1200. doi:  10.1038/cr.2010.145
    [5] Parsons DW, Jones S, Zhang X, et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme[J]. Science, 2008, 321: 1807-1812. doi:  10.1126/science.1164382
    [6] Mardis ER, Ding L, Dooling DJ, et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome[J]. N Engl J Med, 2009, 361: 1058-1066. doi:  10.1056/NEJMoa0903840
    [7] Moeini A, Sia D, Bardeesy N, et al. Molecular Pathogenesis and Targeted Therapies of Intrahepatic Cholangiocarcinoma[J]. Clin Cancer Res, 2016, 22: 291-300. doi:  10.1158/1078-0432.CCR-14-3296
    [8] Tommasini-Ghelfi S, Murnan K, Kouri FM, et al. Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease[J]. Sci Adv, 2019, 5: eaaw4543. doi:  10.1126/sciadv.aaw4543
    [9] Harding JJ, Lowery MA, Shih AH, et al. Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition[J]. Cancer Discov, 2018, 8: 1540-1547. doi:  10.1158/2159-8290.CD-18-0877
    [10] Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation[J]. Cancer Cell, 2010, 18: 553-567. doi:  10.1016/j.ccr.2010.11.015
    [11] Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity[J]. Sci Transl Med, 2017, 9: eaaI2463. doi:  10.1126/scitranslmed.aal2463
    [12] Schvartzman JM, Reuter VP, Koche RP, et al. 2-hydroxyglutarate inhibits MyoD-mediated differentiation by prevent-ing H3K9 demethylation[J]. Proc Natl Acad Sci USA, 2019, 116: 12851-12856. doi:  10.1073/pnas.1817662116
    [13] Lapointe S, Perry A, Butowski NA. Primary brain tumours in adults[J]. Lancet, 2018, 392: 432-446. doi:  10.1016/S0140-6736(18)30990-5
    [14] Su YT, Phan FP, Wu J. Perspectives on IDH Mutation in Diffuse Gliomas[J]. Trends Cancer, 2018, 4: 605-607. doi:  10.1016/j.trecan.2018.06.006
    [15] Huang RY, Young RJ, Ellingson BM, et al. Volumetric analysis of IDH-mutant lower-grade glioma: a natural history study of tumor growth rates before and after treatment[J]. Neuro Oncol, 2020, 22: 1822-1830. doi:  10.1093/neuonc/noaa105
    [16] Molenaar RJ, Radivoyevitch T, Nagata Y, et al. IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors[J]. Clin Cancer Res, 2018, 24: 1705-1715. doi:  10.1158/1078-0432.CCR-17-2796
    [17] Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis[J]. Clin Cancer Res, 2017, 23: 4511-4522. doi:  10.1158/1078-0432.CCR-16-2628
    [18] Haga H, Patel T. Molecular diagnosis of intrahepatic cholangiocarcinoma[J]. J Hepatobiliary Pancreat Sci, 2015, 22: 114-123. doi:  10.1002/jhbp.156
    [19] Saha SK, Zhu AX, Fuchs CS, et al. Forty-Year Trends in Cholangiocarcinoma Incidence in the US: Intrahepatic Disease on the Rise[J]. Oncologist, 2016, 21: 594-599. doi:  10.1634/theoncologist.2015-0446
    [20] Bai X, Zhang H, Zhou Y, et al. Ten-Eleven Translocation 1 Promotes Malignant Progression of Cholangiocarcinoma With Wild-Type Isocitrate Dehydrogenase 1[J]. Hepatology, 2021, 73: 1747-1763. doi:  10.1002/hep.31486
    [21] Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas[J]. Oncogene, 2013, 32: 3091-3100. doi:  10.1038/onc.2012.315
    [22] Tateishi K, Wakimoto H, Iafrate AJ, et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion[J]. Cancer Cell, 2015, 28: 773-784. doi:  10.1016/j.ccell.2015.11.006
    [23] Nagashima H, Lee CK, Tateishi K, et al. Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD(+) to Potentiate the Metabolic Lethality of Alkylating Chemo-therapy in IDH-Mutant Tumor Cells[J]. Cancer Discov, 2020, 10: 1672-1689. doi:  10.1158/2159-8290.CD-20-0226
    [24] McDuff SGR, Dietrich J, Atkins KM, et al. Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV[J]. Cancer Med, 2020, 9: 3-11. doi:  10.1002/cam4.2686
    [25] Yamashita AS, da Costa Rosa M, Borodovsky A, et al. Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide[J]. Neuro Oncol, 2019, 21: 189-200. doi:  10.1093/neuonc/noy146
    [26] Raulet DH. Roles of the NKG2D immunoreceptor and its ligands[J]. Nat Rev Immunol, 2003, 3: 781-790. doi:  10.1038/nri1199
    [27] Zhang X, Kim WJ, Rao AV, et al. In vivo efficacy of decitabine as a natural killer cell-mediated immunotherapy against isocitrate dehydrogenase mutant gliomas[J]. Neurosurg Focus, 2022, 52: E3.
    [28] DiNardo CD, Stein AS, Stein EM, et al. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia[J]. J Clin Oncol, 2021, 39: 57-65.
    [29] Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer[J]. N Engl J Med, 2010, 362: 1273-1281. doi:  10.1056/NEJMoa0908721
    [30] Yang X, Wang J. Precision therapy for acute myeloid leukemia[J]. J Hematol Oncol, 2018, 11: 3. doi:  10.1186/s13045-017-0543-7
    [31] Wang SS, Bandopadhayay P, Jenkins MR. Towards Immunotherapy for Pediatric Brain Tumors[J]. Trends Immunol, 2019, 40: 748-761. doi:  10.1016/j.it.2019.05.009
    [32] Roerden M, Nelde A, Walz JS. Neoantigens in Hematolo-gical Malignancies-Ultimate Targets for Immunotherapy?[J]. Front Immunol, 2019, 10: 3004. doi:  10.3389/fimmu.2019.03004
    [33] Platten M, Bunse L, Wick A, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma[J]. Nature, 2021, 592: 463-468. doi:  10.1038/s41586-021-03363-z
    [34] Kohanbash G, Carrera DA, Shrivastav S, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas[J]. J Clin Invest, 2017, 127: 1425-1437. doi:  10.1172/JCI90644
    [35] Bunse L, Pusch S, Bunse T, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate[J]. Nat Med, 2018, 24: 1192-1203. doi:  10.1038/s41591-018-0095-6
    [36] DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML[J]. N Engl J Med, 2018, 378: 2386-2398. doi:  10.1056/NEJMoa1716984
    [37] Mellinghoff IK, Ellingson BM, Touat M, et al. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma[J]. J Clin Oncol, 2020, 38: 3398-3406. doi:  10.1200/JCO.19.03327
    [38] Andronesi OC, Arrillaga-Romany IC, Ly KI, et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate[J]. Nat Commun, 2018, 9: 1474. doi:  10.1038/s41467-018-03905-6
    [39] Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study[J]. Lancet Gastroenterol Hepatol, 2019, 4: 711-720. doi:  10.1016/S2468-1253(19)30189-X
    [40] Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21: 796-807. doi:  10.1016/S1470-2045(20)30157-1
    [41] Cho YS, Levell JR, Liu G, et al. Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor[J]. ACS Med Chem Lett, 2017, 8: 1116-1121. doi:  10.1021/acsmedchemlett.7b00342
    [42] Chaturvedi A, Herbst L, Pusch S, et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo[J]. Leukemia, 2017, 31: 2020-2028. doi:  10.1038/leu.2017.46
    [43] Fathi AT, DiNardo CD, Kline I, et al. Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study[J]. JAMA Oncol, 2018, 4: 1106-1110. doi:  10.1001/jamaoncol.2017.4695
    [44] Pollyea DA, Tallman MS, de Botton S, et al. Enasi-denib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia[J]. Leukemia, 2019, 33: 2575-2584. doi:  10.1038/s41375-019-0472-2
    [45] Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib[J]. Blood, 2019, 133: 676-687. doi:  10.1182/blood-2018-08-869008
    [46] Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial[J]. Clin Cancer Res, 2021, 27: 4491-4499. doi:  10.1158/1078-0432.CCR-21-0611
    [47] Konteatis Z, Artin E, Nicolay B, et al. Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma[J]. ACS Med Chem Lett, 2020, 11: 101-107. doi:  10.1021/acsmedchemlett.9b00509
    [48] Karpel-Massler G, Nguyen TTT, Shang E, et al. Novel IDH1-Targeted Glioma Therapies[J]. CNS Drugs, 2019, 33: 1155-1166. doi:  10.1007/s40263-019-00684-6
    [49] Fritz C, Portwood SM, Przespolewski A, et al. PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias[J]. Blood Rev, 2021, 45: 100696. doi:  10.1016/j.blre.2020.100696
    [50] Mao Y, Huang X, Shuang Z, et al. PARP inhibitor olaparib sensitizes cholangiocarcinoma cells to radiation[J]. Cancer Med, 2018, 7: 1285-1296. doi:  10.1002/cam4.1318
    [51] Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia[J]. Nat Med, 2015, 21: 178-184. doi:  10.1038/nm.3788
    [52] Morsia E, McCullough K, Joshi M, et al. Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients[J]. Am J Hematol, 2020, 95: 1511-1521. doi:  10.1002/ajh.25978
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