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Updated: Jan 23, 2026
Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics
Danielle Golub1,2, Nishanth Iyengar3, Siddhant Dogra3
1Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
Abstract:
The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. 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. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.
Insights
Isocitrate dehydrogenase (IDH) mutations drive cancer by producing 2-hydroxyglutarate (2HG). Mutant IDH inhibitors show promise for treating IDH-mutant cancers like AML and glioma, with ongoing research into combination therapies.
Area of Science:
- Oncology
- Metabolic pathways
- Epigenetics
Background:
- Neomorphic isocitrate dehydrogenase (IDH) mutations are identified in diverse cancers, altering oncogenesis.
- IDH mutations produce 2-hydroxyglutarate (2HG), disrupting cellular differentiation and contributing to cancer development.
- Small molecule inhibitors offer targeted therapeutic potential for IDH-mutant malignancies.
Purpose of the Study:
- To review molecular pathways and oncogenic consequences of IDH mutations, focusing on glioma and acute myeloid leukemia (AML).
- To systematically review the development and preclinical testing of mutant IDH (mutIDH) inhibitors.
- To discuss clinical data, limitations of monotherapy, and combination strategies for mutIDH inhibitors.
Main Methods:
- Literature review of molecular pathways and oncogenic consequences of IDH mutations.
- Systematic review of mutIDH inhibitor development and preclinical data.
- Review of existing clinical data for mutIDH inhibitors in hematologic and solid tumors.
Main Results:
- IDH mutations lead to 2HG production, impacting metabolic and epigenetic mechanisms.
- Two mutIDH inhibitors, Enasidenib and Ivosidenib, are FDA-approved for relapsed/refractory AML.
- Ongoing trials investigate mutIDH inhibitors in glioma, cholangiocarcinoma, and chondrosarcoma.
Conclusions:
- Mutant IDH inhibitors represent a significant advancement in targeted cancer therapy.
- Further research is needed to overcome limitations of monotherapy and optimize treatment via combination strategies.
- Targeting IDH mutations offers a promising therapeutic avenue for various malignancies.
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