Abstract
Simple SummaryMutations of isocitrate dehydrogenase (IDH) genes are the distinctive genetic feature of lower-grade gliomas (LGGs). Tumor-associated IDH1/2 mutations result in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG), which acts as an oncometabolite causing widespread changes in histone and DNA methylation and altering cellular metabolism. In the present review, we examine the “truncal” role of IDH mutations in gliomagenesis, giving hints on the different therapeutic strategies targeting IDH1/2-mutated gliomas. We analyze in detail, preclinical and, when available, data from clinical trials of specific inhibitors blocking the mutant enzyme, IDH-targeted immunotherapeutic approaches, and agents exploiting cellular metabolic and epigenetic vulnerabilities associated with the IDH mutant phenotype.Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest “driver” genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply “precision oncology” in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.
Highlights
Since the first discovery of isocitrate dehydrogenase (IDH) somatic mutations in 2006, major advances have been made in understanding their contribution to cancer development, providing a strong rationale for pharmacologically targeting the mutant metabolic enzyme.The IDH family includes three different isozymes regulating key metabolic cellular processes, such as the ‘Krebs’ cycle, glutamine metabolism, lipogenesis, and redox balance
Mutations of IDH1 and IDH2 have been identified in over 70% of lower-grade gliomas (LGGs; World Health Organization (WHO) grade II/III) and secondary glioblastoma (GBM) [1,2], and at lower frequencies in a variety of other human malignancies, including acute myeloid leukemia (AML; ≈30%), chondrosarcoma (≈50%), cholangiocarcinoma (≈15–20%), thyroid carcinoma, melanoma, angioimmunoblastic T-cell lymphoma, and in a rare subtype of breast cancer [3–8]
IDH mutations have been subsequently recognized as the distinctive genetic feature of LGGs, occurring in more than 90% of low-grade gliomas (WHO grade II) and in 70% of anaplastic gliomas (WHO grade III) [1]
Summary
Since the first discovery of isocitrate dehydrogenase (IDH) somatic mutations in 2006, major advances have been made in understanding their contribution to cancer development, providing a strong rationale for pharmacologically targeting the mutant metabolic enzyme. The IDH family includes three different isozymes regulating key metabolic cellular processes, such as the ‘Krebs’ cycle, glutamine metabolism, lipogenesis, and redox balance. IDH1-2 is responsible for the NADP-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. Mutations of IDH1 and IDH2 have been identified in over 70% of lower-grade gliomas (LGGs; World Health Organization (WHO) grade II/III) and secondary glioblastoma (GBM) [1,2], and at lower frequencies in a variety of other human malignancies, including acute myeloid leukemia (AML; ≈30%), chondrosarcoma (≈50%), cholangiocarcinoma (≈15–20%), thyroid carcinoma, melanoma, angioimmunoblastic T-cell lymphoma, and in a rare subtype of breast cancer [3–8]. IDH3 is a heterodimer, not structurally related to the other two isoforms, and only rarely mutated in cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
