Faculty Opinions recommendation of Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.

2018 ◽  
Author(s):  
John Lowe
Keyword(s):  
Mutant Idh1

scholarly journals Evaluating Mechanisms of IDH1 Regulation through Site-Specific Acetylation Mimics

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 740
Author(s):  
Joi Weeks ◽  
Alexandra I. Strom ◽  
Vinnie Widjaja ◽  
Sati Alexander ◽  
Dahra K. Pucher ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Translational Regulation ◽  
Catalytic Efficiency ◽  
Low Grade ◽  
Lysine Acetylation ◽  
Site Specific ◽  
Idh1 Mutations ◽  
Mutant Idh1 ◽  
Biochemical Features ◽  
Secondary Glioblastomas

Isocitrate dehydrogenase (IDH1) catalyzes the reversible NADP+-dependent oxidation of isocitrate to α-ketoglutarate (αKG). IDH1 mutations, primarily R132H, drive > 80% of low-grade gliomas and secondary glioblastomas and facilitate the NADPH-dependent reduction of αKG to the oncometabolite D-2-hydroxyglutarate (D2HG). While the biochemical features of human WT and mutant IDH1 catalysis have been well-established, considerably less is known about mechanisms of regulation. Proteomics studies have identified lysine acetylation in WT IDH1, indicating post-translational regulation. Here, we generated lysine to glutamine acetylation mimic mutants in IDH1 to evaluate the effects on activity. We show that mimicking lysine acetylation decreased the catalytic efficiency of WT IDH1, with less severe catalytic consequences for R132H IDH1.

scholarly journals Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1

2010 ◽  
Vol 70 (22) ◽  
pp. 8981-8987 ◽  
Author(s):  
Meghan J. Seltzer ◽  
Bryson D. Bennett ◽  
Avadhut D. Joshi ◽  
Ping Gao ◽  
Ajit G. Thomas ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Mutant Idh1

Application of Mutant IDH1 Antibody to Differentiate Diffuse Glioma From Nonneoplastic Central Nervous System Lesions and Therapy-induced Changes

2010 ◽  
Vol 34 (8) ◽  
pp. 1199-1204 ◽  
Author(s):  
David Capper ◽  
Felix Sahm ◽  
Christian Hartmann ◽  
Richard Meyermann ◽  
Andreas von Deimling ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Diffuse Glioma ◽  
Mutant Idh1 ◽  
Induced Changes

scholarly journals Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

2020 ◽  
Author(s):  
Padma Kadiyala ◽  
Stephen V. Carney ◽  
Jessica C. Gauss ◽  
Maria B. Garcia-Fabiani ◽  
Felipe J. Núñez ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Immunological Memory ◽  
Immune Checkpoint Blockade ◽  
Metabolic Reprogramming ◽  
Lower Grade ◽  
Combination Strategy ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh1 R132h ◽  
Mutant Idh1 ◽  
Promoter Mutations

AbstractMutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas’ subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.Brief SummaryInhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.

scholarly journals From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma

2013 ◽  
Vol 34 (2) ◽  
pp. E2 ◽  
Author(s):  
Gavin P. Dunn ◽  
Ovidiu C. Andronesi ◽  
Daniel P. Cahill
Keyword(s):  
Hypoxia Inducible Factor ◽  
Diagnostic Tools ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Treatment Algorithms ◽  
Recurrent Mutations ◽  
Molecular Landscape ◽  
Mutant Idh1 ◽  
And Function

The characterization of the genomic alterations across all human cancers is changing the way that malignant disease is defined and treated. This paradigm is extending to glioma, where the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioma and other IDH-mutant cancers. The IDH1 mutations are present in the vast majority of low-grade gliomas and secondary glioblastomas. Rapidly emerging work on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome, transcriptional programs, hypoxia-inducible factor biology, and development. In the brief time since its discovery, knowledge of the IDH mutation status has had significant translational implications, and diagnostic tools are being used to monitor its expression and function. The concept of IDH1-mutant versus IDH1-wild type will become a critical early distinction in diagnostic and treatment algorithms.

scholarly journals Multicentric Glioma Develops via a Mutant IDH1-Independent Pathway: Immunohistochemical Study of Multicentric Glioma

Pathobiology ◽  
2016 ◽  
Vol 84 (2) ◽  
pp. 99-107 ◽  
Author(s):  
Vega Karlowee ◽  
Vishwa Jeet Amatya ◽  
Hirofumi Hirano ◽  
Takeshi Takayasu ◽  
Ryo Nosaka ◽  
...  
Keyword(s):  
Immunohistochemical Study ◽  
Multicentric Glioma ◽  
Mutant Idh1

scholarly journals Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

2018 ◽  
Vol 475 (20) ◽  
pp. 3221-3238 ◽  
Author(s):  
Diego Avellaneda Matteo ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
Adam J. Grunseth ◽  
Olga Zagnitko ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Resistance Mutation ◽  
Poor Response ◽  
Fold Increase ◽  
Structural Features ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Dynamics Simulations ◽  
Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

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