Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors

Yosuke Kitagawa; Ami Kobayashi; Daniel P Cahill; Hiroaki Wakimoto; Shota Tanaka

doi:10.1016/j.bbcan.2024.189102

Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors

Biochim Biophys Acta Rev Cancer. 2024 May;1879(3):189102. doi: 10.1016/j.bbcan.2024.189102. Epub 2024 Apr 21.

Authors

Yosuke Kitagawa¹, Ami Kobayashi², Daniel P Cahill³, Hiroaki Wakimoto⁴, Shota Tanaka⁵

Affiliations

¹ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 1138655 Bunkyo-ku, Tokyo, Japan.
² Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 02115 Boston, MA, USA.
³ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA.
⁴ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA. Electronic address: hwakimoto@mgh.harvard.edu.
⁵ Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 7008558, Okayama, Japan.

PMID: 38653436
DOI: 10.1016/j.bbcan.2024.189102

Abstract

Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.

Keywords: D2-hydroxyglutarate (D2-HG); Glioma; Isocitrate dehydrogenase (IDH).

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Glioma* / drug therapy
Glioma* / genetics
Glioma* / pathology
Glutarates / metabolism
Humans
Isocitrate Dehydrogenase* / antagonists & inhibitors
Isocitrate Dehydrogenase* / genetics
Molecular Targeted Therapy
Mutation*

Substances

alpha-hydroxyglutarate