title: Targeting isocitrate dehydrogenase (IDH) in cancer.
abstract: Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG. High levels of 2-HG have been shown to inhibit α-KG dependent dioxygenases, including histone and deoxyribonucleic acid (DNA) demethylases, which play a key role in regulating the epigenetic state of cells. Current targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) selectively inhibit mutant IDH protein and induce cell differentiation in in vitro and in vivo models. Preliminary results from phase I clinical trials with IDH inhibitors in patients with advanced hematologic malignancies have demonstrated an objective response rate ranging from 31% to 40% with durable responses (>1 year) observed. Furthermore, the IDH inhibitors have demonstrated early signals of activity in solid tumors with IDH mutations, including cholangiocarcinomas and low grade gliomas.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|These authors contributed equally to this work.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|These authors contributed equally to this work.
authors.forename: Muhammad Rizwan
authors.initials: MR
authors.lastname: Khawaja
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: DiNardo
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Johnique T
authors.initials: JT
authors.lastname: Atkins
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D002454:Cell Differentiation / Q000235:genetics; D019069:Cell Respiration; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002986:Clinical Trials as Topic; D005977:Glutarates / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007656:Ketoglutaric Acids / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D005977:Glutarates; D006657:Histones; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D009249:NADP; D007521:Isocitrate Dehydrogenase; D056466:Histone Demethylases