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  • Review Article
  • Published:

IDH inhibition in gliomas: from preclinical models to clinical trials

Abstract

Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, d-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.

Key points

  • Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Mutant IDH produces the oncometabolite d-2-hydroxyglutarate (D-2-HG), which induces DNA and histone hypermethylation and interferes with immunity, thereby stimulating tumour growth.

  • In preclinical models, selective inhibitors of mutant IDH were shown to decrease the production of d-2-HG, slow tumour growth and promote cellular differentiation.

  • In early clinical trials, ivosidenib, a mutant IDH1 inhibitor, and vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, were found to reduce D-2-HG concentrations and induce high rates of MRI-detectable glioma stabilization or response.

  • The phase III INDIGO trial has shown superiority of vorasidenib over placebo in residual or recurrent non-enhancing grade 2 gliomas after surgery, thereby raising the prospect of delaying of chemoradiotherapy.

  • Future studies should evaluate vorasidenib in enhancing tumours of different grades of malignancy, investigate novel IDH inhibitors and combination of drugs, and develop advanced tools to monitor response and relapse.

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Fig. 1: Effects of mutant IDH in glioma cells.
Fig. 2: Timeline of development of vorasidenib.

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R.R. designed the manuscript, wrote the clinical parts, and reviewed and edited the manuscript before submission. C.H. wrote the sections on oncogenesis in IDH-mutant gliomas and IDH inhibitors in preclinical models. M.v.d.B. wrote the conclusions. M.P. and R.S. reviewed the entire manuscript before submission.

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Correspondence to Roberta Rudà.

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Competing interests

R.R. has received honoraria for lectures from UCB, Servier, Genenta, Novocure and Curevac. M.v.d.B. reports consulting for Boehringer Ingelheim, F. Hoffman-La Roche, Fore Biotherapeutics, Genenta, Incyte Corporation, AnHeart therapeutics, Mundipharma, SymBio Pharma and Servier Affaires Medicales. M.P. has received honoraria for lectures, consultation or advisory board participation from Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer Ingelheim and Telix, Medscape. R.S. has received honoraria for lectures, consultation or advisory board participation from Celldex Therapeutics, Mundipharma, Puma Technology, Astra Zeneca, Servier and Seagen. C.H. declares no competing interests.

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Rudà, R., Horbinski, C., van den Bent, M. et al. IDH inhibition in gliomas: from preclinical models to clinical trials. Nat Rev Neurol 20, 395–407 (2024). https://doi.org/10.1038/s41582-024-00967-7

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