Abstract
Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.
Highlights
Gliomas are the most common central nervous system (CNS) tumors in adults [1].They can be classified based on the cellular origin of the tumor into astrocytomas, oligodendrogliomas, or ependymomas or on the aggressiveness of the tumor into grade I–IV gliomas
We present an overview of the state-of-the-art of the therapeutic approaches applied in isocitrate dehydrogenases (IDH)-mutant gliomas and provide a summary of both preclinical studies and clinical trials
IDH mutations are highly frequent in lower-grade gliomas and secondary GBMs
Summary
Gliomas are the most common central nervous system (CNS) tumors in adults [1] They can be classified based on the cellular origin of the tumor into astrocytomas, oligodendrogliomas, or ependymomas or on the aggressiveness of the tumor into grade I–IV gliomas. One of the most important diagnostic markers of diffuse glioma is the status of the IDH mutation Both oligodendrogliomas and astrocytomas, either lower-grade (grade II or III) or glioblastomas Lower-grade gliomas (LGG) and primary GBMs make up most of the glioma cases (Figure 1A). Lower-grade gliomas (LGG) and primary GBMs make up most of the2glioma of 21 cases (Figure 1A). IDH mutations are markedly observed in LGGs and secondary GBMs (Figure 1B) and are among the early genetic events in tumor progression
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