Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

Front Oncol. 2019 May 17:9:417. doi: 10.3389/fonc.2019.00417.

Danielle Golub ¹ ², Nishanth Iyengar ³, Siddhant Dogra ³, Taylor Wong ¹, Devin Bready ¹, Karen Tang ² ⁴, Aram S Modrek ⁵, Dimitris G Placantonakis ¹ ⁶ ⁷ ⁸ ⁹

Affiliations

1 Department of Neurosurgery, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
2 Clinical and Translational Science Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
3 New York University School of Medicine, NYU Langone Health, New York, NY, United States.
4 Division of Hematology/Oncology, Department of Pediatrics, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
5 Department of Radiation Oncology, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
6 Kimmel Center for Stem Cell Biology, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
7 Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
8 Brain Tumor Center, New York University School of Medicine, NYU Langone Health, New York, NY, United States.
9 Neuroscience Institute, New York University School of Medicine, NYU Langone Health, New York, NY, United States.

PMID: 31165048 DOI: 10.3389/fonc.2019.00417

Abstract

The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple Cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.

Keywords

IDH; acute myeloid leukemia; enasidenib; glioma; isocitrate dehydrogenase; ivosidenib.

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