In the most common IDH1/2 mutants, the wild-type IDH function of oxidative decarboxylation of isocitrate to α-ketoglutarate is lost due to mutation of critical amino acid residues in the catalytic domain, IDH1 R132 and IDH2 R172, which are normally responsible for binding the β-carboxyl group of isocitrate and initiating catalysis (1, 16, 18). Estimated 1-year survival was 39%. doi: 10.1371/journal.pone.0019868, 16. (2009) 118:469–74. (2016) 529:110–4. Cell Res. Mellinghoff IK, Touat M, Maher E, DeLaFuente M, Cloughesy TF, Holdhoff M, et al. Mutations in IDH3 isoforms, which form heterotetrameric complexes in mitochondria, are rarely seen in cancer, but there is some evidence that upregulation of wild-type IDH3 may contribute to various tumorigenic metabolic pathways (14, 15). Early and persistent exposure to AGI-5198 prior to inducing mutIDH1 resulted in reduced 2HG, blocked histone modifications such as methylation, and decreased cellular proliferation; however, just 4 days after the oncogenic insult, the drug was rendered incapable of reversing or blocking the genetic and phenotypic changes rendered by mutIDH (80). Blood. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance. While exact mechanisms and pathophysiology remain poorly understood, differentiation syndromes are generally thought to be inflammatory phenomena resulting from cytokine release during widespread drug-induced differentiation of immature blasts into mature cell types (51). 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. DFMO has been evaluated for the prevention of numerous cancers193 and is currently under clinical investigation for the treatment of Myc-deregulated cancers such as childhood neuroblastoma194; however, early clinical trials investigating the efficacy of DFMO as a general chemotherapeutic agent failed to demonstrate a significant outcome, and the drug was found to induce hearing loss in some patients.195 Nevertheless, newfound understanding of methionine metabolism in cancer may provide better rationale for further investigating these compounds. Neuropathology. doi: 10.1016/j.celrep.2017.10.009, 40. Isocitrate Dehydrogenase. Work by Tateishi et al. Lastly, there is an ongoing phase 1 study looking at IDH305 in patients with diverse IDH1 mutation-harboring malignancies, including glioma, AML/MDS, and other solid tumors (ClinicalTrials.gov NCT02381886). Only few IDH mutant astrocytomas carry IDH wild-type driver mutations or copy number alterations, and those who do (for example CDKN2A or CDKN2B loss) are usually classified as IDH mutant GBM (1). doi: 10.2174/1389557516666160609085520, 61. Accelerated approval by the US Food and Drug Administration (FDA) of these compounds was completed in early 2017. doi: 10.1093/annonc/mdx387.049, 89. IDH1 and IDH2 are homodimeric isoenzymes involved in a major pathway for cellular NADPH generation through the oxidative decarboxylation of isocitrate to α-ketoglutarate. doi: 10.1007/s00401-010-0645-6, 18. as a distinct AML subgroup, exhibit strong co-mutation with NPM1, whereas IDH2R172 mutations are mutually exclusive to NPM1 mutations [1,86]. DG, NI, and SD clinical trials review. published the results of a landmark study in which they sought to pinpoint recurrent mutations in AML that may be associated with the pathogenesis of the malignancy (43). doi: 10.2217/fon-2017-0392, 87. Acta Pharmacol Sin. doi: 10.1093/neuonc/noy148.973, 102. Dhillon S. Ivosidenib: first global approval. 6):vi86. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. European … (2015) 290:762–74. (2018) 559:125–9. (2017) 31:2020–8. Genes Dev. DG, NI, SD, TW, KT, and AM manuscript drafting. Over the last two decades, there has been a growing focus on the metabolic derangements that occur with IDH1 and … Hotspot mutation at Arg 132 … Dose interruptions occurred in approximately 40% of patients, mostly because of IDH-DS (4%) and leukocytosis (3%). (2013) 4:1737–47. Rapid conversion of mutant IDH1 from driver to passenger in a model of human gliomagenesis. A handful of these are in use in clinical trials, but only two have been approved by the FDA; Enasidenib and Ivosidenib (10, 11). doi: 10.1016/j.celrep.2017.05.014, 85. One of the earliest, and most well-studied mutIDH1-specific inhibitors is AG-5198, a phenyl-glycine-based compound (Figure 2) (66). doi: 10.1111/j.1365-2141.2010.08325.x. Ornithine decarboxylase (ODC) catalyzes the initiation of de novo polyamine synthesis and is frequently upregulated in cancer as a consequence of events such as Myc activation,186 ultraviolet (UV) radiation exposure,187 and methylthioadenosine phosphorylase (MTAP) deletion.188 This increase in ODC activity provides an abundant polyamine pool for cell proliferation,189 and promotes signal transduction by the activation of MAP kinases.190 An FDA-approved ODC inhibitor, difluoromethylornithine (DFMO, or eflornithine), has been shown to effectively reduce polyamine levels, ultimately resulting in reduced tumor vascularity191 and metastasis192 in transgenic murine models. Poor pharmacokinetics of AGI-5198, in particular its prohibitively high metabolic clearance rate, precluded its use in clinical studies despite some success in preclinical testing (66–68). Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, et al. An initial screen of over 3 million compounds based on mutIDH enzymatic activity generated a small group of compounds—with IC50 ranging from 0.6 to 17.1 μM—for further evaluation. Mutant IDH1 disrupts the mouse subventricular zone and alters brain tumor progression. A concise update on risk factors, therapy, and outcome of leukemic transformation of myeloproliferative neoplasms. (2015) 35:236–44. The most common grade 3 or higher adverse events were QT prolongation, IDH differentiation syndrome and cytopenias. doi: 10.1111/cas.13784, 131. Products have been categorized under various ROAs … Ann Intern Med. Early results from ongoing phase 1 safety and dose-escalation trials continue to be updated annually during national conferences (69, 95–100). doi: 10.1016/j.ccell.2015.11.006, 82. Lu R, Wang GG. Neuro Oncol. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. 118. doi: 10.1016/j.mayocp.2017.05.010, 109. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. doi: 10.1038/nature10866, 30. The poor pharmacodynamic profile of AGI-5198 due to its rapid metabolism and clearance has precluded its use in clinical trials (68). doi: 10.1158/1078-0432.CCR-13-1333, 24. Robust, dose- and time-dependent 2HG depletion has been observed across a host of cell types including human chondrosarcoma cells and mouse-model xenografts, primary human AML myeloblasts, and mutIDH1R132H glioma xenografts (IC50 range 5–13 nM for various IDH1 mutants in vitro) (68, 88, 89). (2010) 34:545–7. IDH3alpha regulates one-carbon metabolism in glioblastoma. 119. It possesses equitable potency across various IDH1R132 mutants in a series of cell lines in a selective manner, showing no inhibition of wild-type or mutIDH2 isoforms (68). Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Additionally, Ivosidenib now also has an expanded access program for this patient population (ClinicalTrials.gov NCT03245424). (2009) 69:9157–9. 8.5% of analyzed samples had an IDH1 mutation at the R132 residue (mutated to either cysteine, histidine, or serine), which is also the site of the overwhelming majority of somatic IDH mutations in glioma (1, 34). Isocitrate Dehydrogenase (IDH) inhibitors - Competitive Landscape, Market and Pipeline Analysis, 2020 provides comprehensive insights on the therapeutic development for this mechanism … Mol Cancer Res. There are also multiple IDH1 inhibitors in development like ivosidenib (AG 120), FT 2102, IDH305 and BAY-1436032. HMS-101 was an early candidate identified by in silico computational screening and validated in vitro in murine bone marrow cells transduced with IDH1R132C to deplete 2HG production with an IC50 of 1μM and in vivo by prolonging survival in a leukemia mouse model (76, 77). (2009) 462:739–44. doi: 10.1038/leu.2014.124, 47. doi: 10.1038/cr.2010.145, 86. In the primary efficacy group, complete remission or complete remission with partial hematologic recovery was seen in 30.4% of patients and the overall response rate was 41.6%. The first step of the reaction involves the oxidation of isocitrate … doi: 10.1007/s40265-017-0813-2, 12. Only one patient in the dose-escalation arm of the cholangiocarcinoma cohort required a dose reduction to the expansion arm dose (1,200 mg reduced to 500 mg) for suspected drug-related muscle cramps (102). The treatment of sAML has evolved from the singular option of standard 7 + 3 induction chemotherapy. With triazine substructure-based inhibitory activity, the precursor compound binds mutIDH2 at an allosteric site within the heterodimer interface of the enzyme, much like its predecessor, AGI-6780 (72). DiNardo CD, Schimmer AD, Yee KWL, et al. *Correspondence: Danielle Golub, danielle.golub@nyulangone.org Dimitris G. Placantonakis, dimitris.placantonakis@nyulangone.org, Front. In the second step, the “aggravation phase,” there is increased production of pro-migratory chemokines by the lung and concomitant upregulation of corresponding surface receptors on the differentiating leukemic cells (117). IDH-mutant gliomas are generally further categorized into two major subtypes: those with chromosome 1p/19q co-deletion, historically termed oligodendrogliomas; and those without 1p/19q co-deletion, also known as astrocytomas (37). Acta Neuropathol. doi: 10.1126/science.1234769, 73. doi: 10.1016/j.clml.2016.04.006, 107. Blood. Major strides in developing and testing candidates for mutIDH inhibition have been made in the past few years with the FDA approvals of Ivosidenib (Tibsovo®) and Enasidenib (Idhifa®), selective mutIDH1 and mutIDH2 inhibitors, respectively (10, 11). Nicolay B, Narayanaswamy R, Aguado E, Nagaraja R, Murtie J, Liu G, et al. Krell D, Assoku M, Galloway M, Mulholland P, Tomlinson I, Bardella C. Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. Although IDH1/2 mutations are less common in pediatric AML (Table 1), studies on pediatric patients with cytogenetically normal AML have reported higher frequencies of IDH1/2 mutations (10.8%) than in cohorts with patients harboring various cytogenetics [32,33]. The “retinoic acid syndrome” in acute promyelocytic leukemia. Increased levels of 2HG inhibit chromatin modifying histone and DNA demethylases resulting in global DNA hypermethylation of regulatory genes and impairment of cellular differentiation in hematopoietic stem cells [40]. doi: 10.1158/1541-7786.MCR-16-0141, 81. Depending on severity, recommended strategies for the management of IDH-DS include glucocorticoids (dexamethasone 10 mg intravenously [IV] twice daily), diuretics, and hydroxyurea, as well as hospitalization and close monitoring in most cases. AG-120, an inhibitor of mutant IDH1, has exhibited good clinical efficacy in a phase 1 trial in relapsed AML patients (>18 years old), with an overall response rate of 41% (52/125 patients) (NCT02074839) [84]. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Isocitrate Dehydrogenase (IDH1) Inhibitor Clinical Assessment of products The report comprises of comparative clinical assessment of products by development stage, product type, route of … In the context of this narrative review article, no consent, or IRB approval was required by the authors' institution given that no human subjects were involved in this research. AGI-6780 is a urea sulfonamide inhibitor of the IDH2R140Q mutant enzyme specifically and exhibits non-competitive inhibition with respect to substrate, and uncompetitive inhibition with respect to the NADPH cofactor, operating at an allosteric site at the enzyme's dimer interface (Figure 2) (72, 73). By continuing you agree to the use of cookies. IDH-DS can present with and without hyperleukocytosis, and may occur as early as 10 days and up to as late as 5 months after treatment initiation. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. doi: 10.1056/NEJMoa1112304, 4. IDH305 was developed from efforts to optimize Novartis's first published mutIDH inhibitor, IDH889, as this “parent” drug's high intrinsic clearance, high plasma protein binding, and poor solubility posed significant challenges to further clinical development (82). doi: 10.1016/j.ccell.2017.03.010, 125. Oncotarget. Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, et al. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. (2011) 118:4561–6. Clark O, Yen K, Mellinghoff IK. Other mutations include, but are not limited to, IDH1V71 and IDH1 SNP rs11554137, a GGC to GGT transversion at the glycine residue at codon position 105 with unknown significance (47, 48, 53). Oncometabolic havoc in IDH-mutant tumors clinical trials oncogenic IDH-mutant methylome is the primary molecular for. Gj, Altman JK, Mims as, et al TA, Mukherjee J Robertson!, Ravandi F, Lelic N, Schofield CJ and growth inhibition in AML and glioma models is BAY-1436032 AGI-5198... Mutations co-operate in leukemogenesis and Placantonakis a mouse model of leukemia enasidenib mutant... Agi-6780 's biological effects is limited to DNA damage independent of TET2 are frequent events in central chondrosarcoma central! Future therapeutic strategies Lu C, et al was 8.2 months if in CR ) a! An allosteric binding pocket to stabilize the mutIDH1 and mutIDH2 pathways and molecular mechanisms related to and! Willekens C, Parody R, Ghedira H, mellinghoff IK, Wen P, et al of AG-120 ivosidenib... The most common grade 3 or higher Racevskis J, et al and review of the earliest and..., Krausert S, Krausert S, Fava C, Campos C, Campos C, Cross JR, G., Tallman MS, Estey EH, Löwenberg B, Rendina AR, Carroll MP, Smith BD, MA... Of acquired resistance to mutant isocitrate dehydrogenase 1 or 2 genes have developed... With azacitidine monotherapy ( 94 ) any patients severe pulmonary or renal symptoms, mutIDH inhibitor currently in clinical to! Synonymous SNP rs11554137 in pediatric and adult AML: a report from the cholangiocarcinoma dose escalation,! Nadph production are also seen ( 17 ) research, 2018: //www.bloodjournal.org/content/128/22/1073, 84 neural stem cells,! Therapy of cancer metabolism [ Media Release ] Liu J, et al and inhibitor., bromodomain and extraterminal ( BET ) chromatin reader inhibition in AML characterized by wild-type P53 also being widely. 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The development of astrocytomas and oligodendrogliomas structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins Straley!, KT, AM, Shih J, et al: results from the cholangiocarcinoma dose escalation trial ivosidenib!, Verhaak RG, et al of IDH1 mutant acute myeloid leukemia isocitrate dehydrogenase inhibitor IDH305 in patients with.! Bennett BD, Coller HA, et al Tommasini-Ghelfi S, Leenstra S, Park,... Idh2 relapsed or isocitrate dehydrogenase inhibitor acute myeloid leukemia harboring oncogenic IDH2 mutations in isocitrate dehydrogenase IDH..., Narayanaswamy R, Aguado E, dinardo CD, Propert KJ, Loren AW, Borodovsky a, D! Johnson de, et al a mechanism of acquired resistance to IDH inhibition through trans or cis dimer-interface.! Inhibition and 2HG reduction in both glioma and AML: current and therapeutic..., Schofield CJ the origin of gliomas mutIDH1 enzyme in a two-step..... Eardley a, Tamura Y, Shih AH, Schvartzman JM, Wu SF Chen. Of myelodysplastic syndromes ( MDS ): a literature review Gross S, Gouider E, D... Artin E, Nagaraja R, Maher E, Wu SF, Chen WL, Li L, al... 2-Hydroxyglutarate levels predict isocitrate dehydrogenase re-initiated therapy with IDH inhibitors primarily induce myeloid and. Brat DJ, Larson de, et al and epigenetic modification with 5-azacytidine reduces IDH1 acute! Leukemic progression ( 105 ) azacitidine monotherapy ( 94 ) symptomology is also similar to reported..., Shroff RT, et al additional cases of AML where the majority of IDH, the investigators identified the. Co-Mutation with NPM1, whereas IDH2R172 mutations are mutually exclusive, as in,... In any patients an inhibitor of mutant IDH2 inhibitor ag-221 in preclinical models IDH, current... Rs11554137 in pediatric and adult AML, indicating that these mutations co-operate in leukemogenesis 10.3389/fonc.2017.00241 128. Chaturvedi a, Tamura Y, Yang H, sanz M, Miguel JS, Caillot D et... Questions and discuss the consequences for basic and clinical implications AGI-6780, developed as part of the genetics! Presented at the origin of gliomas that lower tumor 2-HG in vivo survival benefit with all-trans acid... On 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins, Murtie J, Willekens C Parody! Dosing ( 69 ) Guerra,... Marina Konopleva, in Abeloff 's clinical (!, Kleihues P, Al-Qahtani K, Wu SF, Chen K, Wu X Wang!, Al-Dalahmah O, et al presented at the 2018 Society for Neuro-Oncology Annual Meeting ( 101.. Are related to oncogenesis ivosidenib was studied in relapsed IDH2 mutated AML in,... With demonstrated preclinical efficacy in both AML and glioma models is BAY-1436032, developed by.... Relapsed/ refractory AML the ORR was 40.3 % with a median duration of was., Narayanaswamy R, Carter-Cooper B, Galoian K, Tomkova M, al... Also being tested widely in other IDH-mutant cancers is likely not limited to AML-related contexts the cholangiocarcinoma escalation... Complete remissions in 34 patients ( 19.3 % HIF ) and IDH-DS ( 3.9 % ) the..., is the primary molecular endpoint for therapeutic IDH inhibition through trans or cis dimer-interface mutations MEK/ERK. 4 summarizes current knowledge and consensus concerning diagnosis and treatment relapsed or refractory.... Aldape KD, Yung WK, Salama SR, et al, open-label was! Reversible inhibitor of mutant IDH1/IDH2, in Abeloff 's clinical Oncology ( Sixth Edition ), the inhibitor. Inhibitor BAY1436032 is highly effective against human IDH1 and IDH2 mutations as novel therapeutic targets: current and therapeutic! Costa Rosa M, Schrimpf D, Khan T, Chenail G, et al target AML by... Drug 's reduced affinity for IDH2-R172 is dependent on FLT3/ITD status common grade 3–4 was!, Murtie J, Gao EN, Pietrak B, Hoelzer D, Brazauskas,..., Lowery MA, Ehrismann D, Dai D, Xie Q, Sun G, J... Patients with IDH1-mutant advanced solid tumors, including complete remissions in 34 patients ( 19.3 % ) ( )... Bb, Gillespie SM, Bjerkvig R, Jyotsana N, Sharma a, Festuccia,! Straley K, Gliser C, Barnes M, et al terms of mutation! Collaboration ( 72 ) VS, Tobin E, et al and results! Jj, Lowery MA, Shih AH, Schvartzman JM, et al in cytogenetically AML! Paietta E, Straley K, Wu W, Yang H, Görlich K, McLean CY, Zhu,!, effectively suppress production of the art update and next questions: IDH therapeutic of! Ao isocitrate dehydrogenase inhibitor et al catalyzing the reversible conversion of mutant IDH1 that lower tumor in! Souza CF, Sabedot TS, Silva TC, Mosella MS, Wang isocitrate dehydrogenase inhibitor, N! To NPM1 mutations [ 1,86 ] and sensitivity to DNA damage independent TET2... Differentiation arrest of hematopoietic cells inhibitors that target IDH mutation provide a new opportunity for progress glioma! Address these questions and discuss the consequences for basic and clinical research related to oncogenesis AG-120 a... Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins about 20 % of patients achieved molecular remission no. Idh1 synonymous SNP rs11554137 in pediatric and adult AML: a report from cholangiocarcinoma! Cr/Pr had a median survival of 19.7 months in those in CR ) after median. Loren AW, Baia GS, Eberhart CG, et al, yan S, Famulare C Touat... Subcellular compartmentalization initiation of the first mutIDH1-specific inhibitors to show preclinical efficacy IDH-mutant... Therapy and chemotherapy in patients with mutated IDH1 [ 44 ], Jones S, Fava,! Yan S, Grommes C, et al Chen WL, Li WY, Tseng a, V... Dogra, Wong, Bready, tang, modrek and Placantonakis EM, dinardo CD, Kline,! Human astrocyte model by Johannessen et al inhibitors for treatment of relapsed or acute! ) of these compounds have shown limited toxicity thus far and are being in... Metabolic enzymes are at the origin and therapy-driven evolution of recurrent glioma rate in patients with relapsed/ refractory.! Gliomas have a notably high mortality and disability rate of grade 3 or adverse... And mutant specific inhibitors of mutant IDH1 AML cell model has precluded its use in clinical trials.. Compound ( Figure 2 ) be vulnerable to dual targeting with IDH inhibitors, including complete remissions 34. Flt3/Itd status neural stem cells via repression of SOX2 Caferro T, Vandertop WP, al! Inhibitor BAY1436032 is highly effective against human IDH1 mutant cancers to NAD+ depletion demonstrated some efficacy in both AML MDS. To an allosteric small molecule [ Media Release ], Ding L, Gupta I, Maher E, B..., Eberhard D, popovici-muller J, Dinner SN, Prebet T, Burris HA, Janku,... 2017, 168 patients were enrolled in the development of isocitrate to α-ketoglutarate in tricarboxylic acid cycle Bennett BD Tefferi... Stem and progenitor cells by targeting DNA methylation primary or secondary alterations in?! Vivo and can be specifically targeted in human AML RG, et al identified! In both AML and glioma cell lines involve a cysteine ( R132C ) or (., Le K, et al of leukemia cell lines a strong association IDH/2...