Journal article
Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma
Neuro-oncology (Charlottesville, Va.)
06/25/2026
DOI: 10.1093/neuonc/noag142
PMID: 42351295
Abstract
Diffuse midline glioma (DMG) is a lethal pediatric brain tumor, driven by profound epigenetic dysregulation, raising the possibility that targeting epigenetic regulators such as histone deacetylases (HDACs) could provide a therapeutic benefit. However, despite preclinical activity, currently available HDAC inhibitors have shown limited clinical translation due to poor central nervous system (CNS) penetration and a lack of HDAC isoform selectivity.
We combined CRISPR/Cas9 screening and pharmacologic HDAC inhibition to identify isoform-specific dependencies in DMG cell lines. Mechanistic studies were performed using bulk RNA-seq and HiChIP, and therapeutic efficacy was evaluated in orthotopic patient-derived xenograft mouse models.
We identify that the nuclear-localized Class I HDAC isoforms are dependencies in DMG and demonstrate that HDAC2 represents a selective dependency that is highly expressed in patient tumors. We further identify a CNS-penetrant HDAC inhibitor, Compound 26, with preferential HDAC1/2 isoform selectivity. Transcriptomic and chromatin conformation analyses reveal that Compound 26 induces rapid transcriptional reprogramming, restores physiologic pontine histone patterns, and induces cell cycle arrest through chromatin reorganization. Consistent with these effects, Compound 26 slows DMG growth in vitro and in orthotopic in vivo models.
Our findings establish HDAC2 as a critical and therapeutically actionable dependency in DMG. Genetic or pharmacological targeting of HDAC2 disrupts DMG chromatin architecture and induces cell cycle arrest. The HDAC1/2-selective inhibitor Compound 26 exhibits favorable CNS-penetration, tolerability, and antitumor activity in disease-relevant patient-derived xenograft models. Collectively, these data support isoform-selective HDAC inhibition as a rational strategy to overcome the translational limitations of pan-HDAC inhibitors in DMG.
Details
- Title: Subtitle
- Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma
- Creators
- Andrew Groves - Broad InstituteOrville O Kirkland - Harvard UniversityCostanza Lo Cascio - Broad InstituteXiuqi Wang - Harvard UniversityCaleb Heaslip - Harvard UniversityJoana Graca Marques - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterChen Song - Harvard UniversityRebecca Poetschke - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterTingjian Wang - Dana-Farber Cancer InstituteDiana H Chin - Case Western Reserve UniversityYaw Asante - Case Western Reserve UniversityQi Liu - Harvard UniversityHyunmin Kim - Case Western Reserve UniversityShanqing Gu - Case Western Reserve UniversityMaria Trissal - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterJenna Labelle - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterGustavo Alencastro Veiga Cruzeiro - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterKristen L Jones - Dana-Farber Cancer InstituteAmy B Cameron - Dana-Farber Cancer InstituteLouise M Clark - Dana-Farber Cancer InstituteBrittaney Leeper - Dana-Farber Cancer InstituteQuang-De Nguyen - Dana-Farber Cancer InstituteBerkley E Gryder - Case Western Reserve UniversityMariella G Filbin - Dana-Farber/Boston Children's Cancer and Blood Disorders CenterJun Qi - Dana-Farber Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Neuro-oncology (Charlottesville, Va.)
- DOI
- 10.1093/neuonc/noag142
- PMID
- 42351295
- ISSN
- 1523-5866
- eISSN
- 1523-5866
- Publisher
- Oxford University Press
- Grant note
- Curing Kids Cancer Foundation Wong Family Translational Award ChadTough Defeat DIPG Foundation V foundation Andruzzi Foundation The Cure Starts Now Alex's Lemonade Stand Foundation IronMatt Foundation Pediatric Brain Tumor Foundation/Musella Foundation for Brain Tumor Research & Information Inc. Sontag Foundation B+ Foundation Solving Kids' Cancer, Inc./The Bibi Fund Burroughs Wellcome Fund Ependymoma Foundation National Cancer Institute The Caroline Mortimer Fund St. Baldrick Foundation
This work was supported by generous funding from: Pediatric Brain Tumor Foundation/Musella Foundation for Brain Tumor Research & Information Inc. (A.G., M.G.F.); ChadTough Defeat DIPG Foundation (A.G., M.G.F.); The Cure Starts Now (M.G.F.); Andruzzi Foundation (M.G.F.); Alex's Lemonade Stand Foundation (M.G.F., J.Q., B.E.G.); John W. and Pamela A. Cuming (M.G.F.); Solving Kids' Cancer, Inc./The Bibi Fund (M.G.F.); V foundation (M.G.F and J.Q.); National Cancer Institute (M.G.F., B.E.G.); B+ Foundation (B.E.G.); IronMatt Foundation (J.Q.); St. Baldrick Foundation (J.Q.); Wong Family Translational Award (J.Q.); Ependymoma Foundation (J.Q. and M.G.F); Curing Kids Cancer Foundation (J.Q.); and The Caroline Mortimer Fund (M.G.F.). M.G.F. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund., the Distinguished Scientist Award from the Sontag Foundation, and the A-Award from the Alex's Lemonade Stand Foundation.
- Language
- English
- Electronic publication date
- 06/25/2026
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9985179685102771
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