Therapeutic strategies for downregulating isocitrate dehydrogenase in the treatment of glioblastoma multiforme

Abstract

IDH-wildtype glioma (Glioblastoma) is the most lethal primary brain tumor in adults, with a median survival of 12–15 months despite optimal treatment. The isocitrate dehydrogenase (IDH) enzyme family, particularly IDH1, plays a central role in Glioblastoma Multiforme (GBM) pathobiology by regulating cellular redox homeostasis, NADPH production, and metabolic adaptation. In IDH-wildtype GBM, which constitutes the majority of primary cases, IDH1 significantly contributes to antioxidant defenses, thereby conferring resistance to radiotherapy, temozolomide (TMZ), and other chemotherapeutic agents. In contrast, IDH-mutant lower-grade gliomas and secondary GBMs harbor gain-of-function mutations that induce CpG island hypermethylation through the production of the oncometabolite 2-hydroxyglutarate (2-HG), resulting in epigenetic dysregulation. The dual mechanistic roles of IDH in GBM biology present distinct therapeutic vulnerabilities. This review evaluates three principal therapeutic strategies to modulate IDH in GBM: (1) small molecule inhibitors targeting IDH-mutants, including FDA-approved agents ivosidenib and vorasidenib, while noting the absence of FDA-approved agents for IDH-wildtype GBM and the ongoing preclinical investigation of IDH1-wildtype targeting; (2) gene manipulation techniques, such as RNA interference (RNAi) and CRISPR-Cas9-mediated knockout; and (3) nanomedicine-based delivery systems, including lipid nanoparticles (LNPs) and exosomes, designed to traverse the blood-brain barrier (BBB) and enable tumor-targeted delivery of therapeutic agents. The review aims to establish a framework for combination therapies directed at IDH in GBM, with a focus on improving clinical outcomes.