<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications?
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...
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doaj-d2113094346f4988aadbcc8aae38c4452021-07-23T13:31:43ZengMDPI AGBiomedicines2227-90592021-07-01979979910.3390/biomedicines9070799<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications?Alisan Kayabolen0Ebru Yilmaz1Tugba Bagci-Onder2Brain Cancer Research and Therapy Lab, Koç University School of Medicine, 34450 Istanbul, TurkeyBrain Cancer Research and Therapy Lab, Koç University School of Medicine, 34450 Istanbul, TurkeyBrain Cancer Research and Therapy Lab, Koç University School of Medicine, 34450 Istanbul, TurkeyDiscovery 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 <i>IDH</i>-mutant gliomas appear to be different from those in <i>IDH</i>-wildtype gliomas. <i>IDH</i> 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 <i>IDH</i> 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 <i>IDH</i>-mutant gliomas.https://www.mdpi.com/2227-9059/9/7/799isocitrate dehydrogenase (IDH)mutationsgliomaglioblastomatherapeuticsclinical trials |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alisan Kayabolen Ebru Yilmaz Tugba Bagci-Onder |
spellingShingle |
Alisan Kayabolen Ebru Yilmaz Tugba Bagci-Onder <i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? Biomedicines isocitrate dehydrogenase (IDH) mutations glioma glioblastoma therapeutics clinical trials |
author_facet |
Alisan Kayabolen Ebru Yilmaz Tugba Bagci-Onder |
author_sort |
Alisan Kayabolen |
title |
<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? |
title_short |
<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? |
title_full |
<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? |
title_fullStr |
<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? |
title_full_unstemmed |
<i>IDH</i> Mutations in Glioma: Double-Edged Sword in Clinical Applications? |
title_sort |
<i>idh</i> mutations in glioma: double-edged sword in clinical applications? |
publisher |
MDPI AG |
series |
Biomedicines |
issn |
2227-9059 |
publishDate |
2021-07-01 |
description |
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 <i>IDH</i>-mutant gliomas appear to be different from those in <i>IDH</i>-wildtype gliomas. <i>IDH</i> 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 <i>IDH</i> 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 <i>IDH</i>-mutant gliomas. |
topic |
isocitrate dehydrogenase (IDH) mutations glioma glioblastoma therapeutics clinical trials |
url |
https://www.mdpi.com/2227-9059/9/7/799 |
work_keys_str_mv |
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