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Updated: Feb 26, 2026
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
Isocitrate dehydrogenase mutation as a therapeutic target in gliomas
Catherine H Han1, Tracy T Batchelor2
1Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA; Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Abstract:
Isocitrate dehydrogenases (IDH) are important enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. More than 80% of low-grade gliomas and secondary glioblastoma (GBM) harbor an IDH mutation. IDH mutations involve the catalytic pocket of the enzyme and lead to a neomorphic ability to produce 2-hydroxyglutarate (2HG) while oxidizing NADPH to NADP+. 2HG is considered as an 'oncometabolite' which is thought to be responsible for many, if not all, biologic effects of IDH mutations. 2HG accumulation competitively inhibits α-KG-dependent dioxygenases, including histone lysine demethylases and DNA demethylases, resulting in a hypermethylation phenotype with alterations in cellular epigenetic status as well as a block in cellular differentiation. IDH mutations have been suggested as an important early event in tumorigenesis, however it remains unclear whether IDH mutation by itself causes cancer or if it requires other oncogenic events to initiate tumorigenesis. Significant efforts have been made to better understand the mechanisms of IDH mutations in tumor initiation and progression, and to develop targeted therapies for IDH-mutated tumors. This review provides an overview of the function of mutant IDH, and the current understanding of the role IDH mutations play in gliomagenesis. In addition, several potential therapeutic strategies for IDH-mutant gliomas, including mutant IDH inhibitors which have entered clinical evaluation in glioma patients, will be discussed.
Insights
Mutant isocitrate dehydrogenases (IDH) produce an oncometabolite, 2-hydroxyglutarate (2HG), driving gliomagenesis through epigenetic alterations. Therapies targeting IDH mutations are under clinical investigation for glioma patients.
Area of Science:
- Biochemistry
- Oncology
- Epigenetics
Background:
- Isocitrate dehydrogenases (IDH) enzymes are crucial for cellular metabolism, producing NADPH.
- Mutations in IDH are prevalent in low-grade gliomas and secondary glioblastomas (GBM).
- IDH mutations confer a neomorphic function, producing 2-hydroxyglutarate (2HG), an oncometabolite.
Purpose of the Study:
- To review the function of mutant IDH and its role in gliomagenesis.
- To explore the biological effects of 2HG accumulation.
- To discuss therapeutic strategies for IDH-mutant gliomas.
Main Methods:
- Review of existing literature on IDH mutations in gliomas.
- Analysis of the biochemical pathways affected by 2HG.
- Examination of current and emerging therapeutic approaches.
Main Results:
- 2HG inhibits α-KG-dependent dioxygenases, leading to hypermethylation and blocked cellular differentiation.
- IDH mutations are implicated as early events in tumorigenesis, though their sole causative role is debated.
- Targeted inhibitors of mutant IDH are in clinical trials for glioma patients.
Conclusions:
- IDH mutations significantly alter cellular epigenetics and promote gliomagenesis.
- Understanding 2HG's role is key to developing effective treatments.
- Targeted therapies show promise for IDH-mutant gliomas.
