Mutant Isocitrate Dehydrogenase 1 Expression Enhances Response of Gliomas to the Histone Deacetylase Inhibitor Belinostat

• Type of Material: Article
• Authors: Chi-Ming Chang, Emory University; Karthik K Ramesh, Emory University; Vicki Huang, Emory University; Saumya Gurbani, Emory University; Lawrence R Kleinberg, Johns Hopkins University; Brent Weinberg, Emory University; Hyunsuk Shim, Emory University; Hui-Kuo Shu, Emory University
• Language: English
• Date: 2023-06-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/tomography9030077
• Title of Journal or Parent Work: Tomography
• Volume: 9
• Issue: 3
• Start Page: 942
• End Page: 954
• Grant/Funding Information: This research was funded by the National Institutes of Health, grants U01 CA172027 (H.-K.G.S. and H.S.) and U01 CA264039 (H.S.). This work is also supported through a predoctoral fellowship F31CA247564 (K.K.R.).
• Keywords: Humans; IDH; glioblastoma; Brain Neoplasms; Histone Deacetylase Inhibitors; sMRI; Glioma; HDAC; Isocitrate Dehydrogenase
• Research Categories: Engineering, Biomedical; Health Sciences, Oncology

Abstract

Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration—converting arginine 132 to histidine—within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.