IDH inhibition in gliomas: from preclinical models to clinical trials

• Published in: Nature reviews. Neurology 2024-07, Vol.20 (7), p.395-407
• Main Authors: Rudà, Roberta, Horbinski, Craig, van den Bent, Martin, Preusser, Matthias, Soffietti, Riccardo
• Format: Article
• Language: English
• Subjects: 631/378/1689/178; 692/617/375/1922; Animals; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Clinical trials; Clinical Trials as Topic; Dehydrogenases; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glioma; Glioma - drug therapy; Glioma - genetics; Humans; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - genetics; Medicine; Medicine & Public Health; Mutation; Neurology; Review Article; Tumors
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/s41582-024-00967-7

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. 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. Small-molecule inhibitors of mutant IDH are emerging as a new therapeutic strategy for IDH -mutant cancers, and this Review charts their pathway of development for 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 stabi