Emerging Roles of Wild-type and Mutant IDH1 in Growth, Metabolism and Therapeutics of Glioma

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Matthew Garrett
Yuki Fujii
Natsuki Osaka
Doshun Ito
Yoshihisa Hirota
Atsuo Sasaki


Glioblastoma is one of the most devastating human malignancies and is categorized into primary and secondary glioblastoma subtypes that develop through different genetic pathways. Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key enzymes linking cellular metabolism to epigenetic regulation and redox states. Hot spot mutations of IDH1 is early and frequent genetic alterations in secondary glioblastoma as well as in grade II and III glioma and represent a major biomarker with diagnostic, prognostic, and predictive implications. Mutant IDH proteins acquire neomorphic enzymatic activity to produce D-2-hydroxyglutarate, a putative oncometabolite that could induce epigenetic changes at DNA and RNA levels. On the other hand, recent studies show that primary glioblastoma increases expression of wild-type IDH1, which confers therapeutic resistance. In this chapter, we introduce the current understanding of the biological roles of wild-type and mutant IDH enzymes in glioblastoma. We discuss the challenges hampering the development of IDH targeted therapeutics and the current status of IDH1 mutant inhibitor development.


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Chapter 4