Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials

Abstract

Isocitrate dehydrogenase (IDH) is a key enzyme in normal metabolism and homeostasis. However, mutant forms of IDH are also defining features of a subset of diffuse gliomas. In this review, we highlight current techniques targeting IDH-mutated gliomas and summarize current and completed clinical trials exploring these strategies. We discuss clinical data from peptide vaccines, mutant IDH (mIDH) inhibitors, and PARP inhibitors. Peptide vaccines have the unique advantage of targeting the specific epitope of a patient’s tumor, inducing a highly tumor-specific CD4+ T-cell response. mIDH-inhibitors, on the other hand, specifically target mutant IDH proteins in cancer cell metabolism and thus help halt gliomagenesis. We also explore PARP inhibitors and their role in treating diffuse gliomas, which exploit IDH mutant diffuse gliomas by allowing the persistence of unrepaired DNA complexes. We summarize various completed and current trials targeting IDH1 and IDH2 mutations in diffuse gliomas. Therapies targeting mutant IDH have significant promise treating progressive or recurrent IDH-mutant gliomas and may significantly change treatment paradigms in the next decade.

Evolution of the meta-neurosurgeon: A systematic review of the current technical capabilities, limitations, and applications of augmented reality in neurosurgery

“…Furthermore, data from multiple imaging modalities can be combined into one projection to allow visualization of critical structures such as deep nuclei and white matter tracts in conjunction with intraoperative 5-ALA fluorescence. [ 37 , 47 ]…”

Vorasidenib: A promising therapeutic breakthrough for diffuse isocitrate dehydrogenase mutant gliomas

“…The given protocol does not reach the maximum allowable dose. 2 Patients with non-enhancing gliomas had a median progression-free survival of 36.8 months, while those with enhancing gliomas had a median survival of 3.6 months. In general, this study provided evidence in favor of Vorasidenib, being a sound therapy option for non-enhancing, IDH1-or IDH2-mutated glioma.…”

“…IDH1, IDH2, and IDH3 are the three existing isoforms. 2 Mutations in isoforms of IDH1 and IDH2, that are heterozygous lead to the formation of oncogenic d-2-hydroxyglutarate (2-HG), 3 causing different malignant growth counting cholangiocarcinoma, glioma and acute myeloid leukemia (AML). This transpires in about 80% of the patients suffering from LLG.…”

“…3 In patients with recurrent or progressive non-enhancing mIDH LGG when treated with vorasidenib it was observed that the drug was highly compatible and even displayed an early antitumor action in them. 2 Vorasidenib, which is an inhibitor of IDH1/ IDH2 expresses the ability to penetrate the CNS and research is currently ongoing to assess its potential as a therapeutic option for glioma with IDH mutation. In clinical trials, phase I with vorasidenib, as a salvage treatment was performed in which 93 patients were enrolled in this study trial with IDH1 or IDH2 mutation, and a total of 52 patients were diagnosed with glioma (both non-enhancing and enhancing gliomas) from 2015 to 2017 in a dose-escalation trial.…”

Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms

“…Mutations at R132 drive >85% lower grade and secondary gliomas 6 and ∼40% of cartilaginous tumors 7 , with R132H typically the most common 8,9 . These mutated enzymes have been successfully therapeutically targeted, with several FDA-approved allosteric selective inhibitors in use and more in clinical trials (recently reviewed in 10–12 ).…”