Dear Editor,
The most common type of major malignant tumor of the brain includes gliomas, which are marked by diffuse invasion of malignant cells in the brain. Grade II and grade III diffuse gliomas classified by the World health organization (WHO) are also known as lower-grade gliomas LLG. These tumors are seen more frequently in younger people, show a slower growth rate, and mostly does not appear on contrast enhancement on T1-weighted brain MRI in the beginning. Current treatment includes chemotherapy, radiation, and maximally safe tumor resection. However, there is a high chance of recurrence and transformation of LLG into a more aggressive tumor. The advanced treatment outlook is to attack mutant genetic changes that are causing gliomas in the initial stage to minimize the use of harmful therapies and to hinder its progression to a higher tumor grade. 1
Isocitrate dehydrogenase (IDH), is an important enzyme having a major role in the tricarboxylic cycle as well as controlling the redox cofactor in between mitochondria and cytosol. 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. The buildup of 2-HG leads to the inhibition of over 60 α-ketoglutarate–dependent enzymes resulting in disturbed cellular differentiation and tumor growth. 1
Scientists are actively exploring the use of pharmacological inhibitors to target mutant isocitrate dehydrogenase (mIDH) enzymes as a potential therapeutic approach. Exploratory studies of mIDH1/2-driven leukemia, cholangiocarcinoma, and glioma, inhibiting mIDH1/2 enzymes have been found to promote cellular differentiation. Moreover, clinical studies have shown promising results in patients with mIDH1 or mIDH2 mutated relapsed or refractory AML, as they have demonstrated positive responses to isoform-selective inhibitors of mIDH1 and mIDH2, respectively. 1
Vorasidenib is an up-and-coming dual brain-penetrant mIDH1/2 inhibitor, treating low-grade mIDH gliomas, that is now in the late stage of development showing good therapeutic activity in early clinical trials. According to an analysis of post-drug treatment tumor samples collected by excision in a perioperative investigation, vorasidenib significantly lowers 2-HG levels by >90% in mIDH glioma patients. 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. Initially, patients were administered a daily dosage of 25 mg of Vorasidenib which was gradually increased to 300 mg. For the phase II trial, the primary emphasis of the study was on evaluating the safety aspects, drug tolerance, its side effects, the maximum tolerable dose, and the recommended dose. The secondary focus of the study included pharmacokinetic and pharmacodynamics characteristics. 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. Overall, the preliminary research confirmed the predominant protection and inceptive efficacy of Vorasidenib, an IDH inhibitor, for treating diffuse IDH mutant gliomas. 2
Footnotes
Author contributions: Dr Amna came up with the topic and paraphrased the manuscript. Dr.Faiza Made a substantial contribution by paraphrasing the manuscript. Dr Wahid & Dr.Fatima equally divided the work among them, they did the literature search on different sites i.e Pubmed, Google Scholar and Newsletters. They also extracted the relevant data which was required as per the topic and drafted the article.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Abdul Wahid https://orcid.org/0000-0003-0265-8781
References
- 1.Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res 2021; 27(16): 4491–4499. DOI: 10.1158/1078-0432.CCR-21-0611 [DOI] [PMC free article] [PubMed] [Google Scholar]
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