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Novel IDH1-Targeted Glioma Therapies

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Abstract

Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H). Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis. Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild-type tumors. Recognition of the high frequency of IDH mutations in glioma [and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma] have led to the development of a number of targeted agents that can inhibit these enzymes. Enasidenib and ivosidenib have both gained regulatory approval for IDH mutant AML. Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG-881, BAY1436032, and DS1001). A marked clinical problem in the development of these agents is overcoming the blood–brain barrier. An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target poly (ADP-ribose) polymerase (PARP), glutamine metabolism, and the Bcl-2 family of proteins. We conclude that within the last decade, several approaches have been devised to therapeutically target the IDH1 mutation, and that, potentially, both IDH1 inhibitors and synthetic lethal approaches might be relevant for future therapies.

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Authors and Affiliations

  1. Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, P&S Rm. 15-415, New York, NY, 10032, USA

    Trang T. T. Nguyen & Markus D. Siegelin

  2. Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany

    Georg Karpel-Massler

  3. Department of Biological Sciences, Bronx Community College, City University of New York, Bronx, NY, USA

    Enyuan Shang

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  1. Georg Karpel-Massler
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  2. Trang T. T. Nguyen
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  4. Markus D. Siegelin
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Correspondence to Markus D. Siegelin.

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Funding

Markus D. Siegelin: NIH NINDS R01NS095848, R01NS102366, K08NS083732, Louis V. Gerstner Jr. Scholars Program (2017–2020) and American Brain Tumor Association Discovery Grant 2017 (DG1700013). Trang T. T. Nguyen: American Brain Tumor Association Basic Research Fellowship (BRF1900018).

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Georg Karpel-Massler, Trang T. T. Nguyen, Enyuan Shang, and Markus D. Siegelin declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Karpel-Massler, G., Nguyen, T.T.T., Shang, E. et al. Novel IDH1-Targeted Glioma Therapies. CNS Drugs 33, 1155–1166 (2019). https://doi.org/10.1007/s40263-019-00684-6

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