Related Experiment Video
Updated: Jul 18, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma
Alyssa Noll1, Carrie Myers2, Matthew C Biery2
1Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Molecular and Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA, USA.
Abstract:
Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
Insights
Constitutional mismatch repair deficiency (CMMRD) drives hypermutant pediatric gliomas. HDAC inhibitors like quisinostat show preclinical efficacy, with MMR-deficient DIPG models demonstrating increased sensitivity, supporting clinical translation.
Area of Science:
- Oncology
- Cancer Biology
- Epigenetics
Background:
- Constitutional mismatch repair deficiency (CMMRD) is a rare cancer predisposition syndrome.
- CMMRD is linked to hypermutant pediatric high-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), with poor prognoses.
- Histone deacetylase (HDAC) inhibition is a potential therapeutic strategy for these aggressive tumors.
Purpose of the Study:
- To evaluate the preclinical efficacy of HDAC inhibitors against hypermutant DIPG.
- To identify specific HDAC inhibitors effective against hypermutant DIPG models.
- To investigate the role of mismatch repair (MMR) deficiency in DIPG sensitivity to HDAC inhibition.
Main Methods:
- Screening of a biopsy-derived hypermutant DIPG cell line (PBT-24FH) against a panel of HDAC inhibitors in vitro.
- In vivo efficacy studies using quisinostat in a PBT-24FH flank tumor model.
- RNA sequencing to analyze gene expression changes induced by quisinostat.
- Testing quisinostat efficacy in genetically-induced MMR-deficient DIPG flank tumor models.
Main Results:
- Quisinostat and romidepsin demonstrated low nanomolar IC50 values against PBT-24FH cells in vitro.
- Quisinostat treatment led to near-complete tumor regression in the PBT-24FH flank model in vivo.
- Quisinostat induced significant changes in gene expression, including upregulation of neural and pro-inflammatory genes.
- MMR-deficient DIPG models showed increased sensitivity to quisinostat in vivo.
Conclusions:
- Quisinostat exhibits preclinical efficacy against hypermutant DIPG.
- HDAC inhibition represents a promising epigenetic targeting strategy for hypermutant pediatric cancers, including DIPG.
- Further clinical investigation of HDAC inhibitors for pontine high-grade gliomas and other hypermutant CNS tumors is warranted.
More Related Videos
09:43Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
09:17Characterization of the Effects of Migrastatic Inhibitors on 3D Tumor Spheroid Invasion by High-resolution Confocal Microscopy
Published on: September 16, 2019