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Updated: Dec 2, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Optimal therapeutic targeting by HDAC inhibition in biopsy-derived treatment-naïve diffuse midline glioma models
Nicholas A Vitanza1,2, Matt C Biery1, Carrie Myers1
1Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Background:
Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response.
Methods:
HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response.
Results:
Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth.
Conclusions:
Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.
Insights
New HDAC inhibitors, quisinostat and romidepsin, show promise against Diffuse Midline Gliomas (DMGs). These findings identify potential biomarkers for this aggressive brain cancer, offering hope for improved treatments.
Area of Science:
- Neuro-oncology
- Epigenetics
- Pharmacology
Background:
- Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a very poor prognosis, with a 5-year survival rate under 2%.
- The majority of these aggressive brain tumors harbor H3 K27M mutations affecting histone tails, making them targets for epigenetic therapies.
- Histone deacetylase inhibitors (HDACi), such as panobinostat, are being investigated for DMG treatment.
Purpose of the Study:
- To identify and validate novel, effective HDAC inhibitors for Diffuse Midline Gliomas (DMGs).
- To discover predictive biomarkers of response to HDAC inhibitor therapy in DMG models.
Main Methods:
- Tested HDAC inhibitors (quisinostat, romidepsin) in biopsy-derived, treatment-naïve in vitro and in vivo DMG models.
- Utilized RNA sequencing to compare drug efficacy and identify biomarkers.
- Assessed tumor growth inhibition in vivo.
Main Results:
- Quisinostat and romidepsin demonstrated potent efficacy with low nanomolar IC50 values.
- Transcriptome analysis revealed shared biological effects between quisinostat and panobinostat.
- Overexpression of TNNT1 and downregulation of COL20A1 were identified as potential biomarkers across multiple HDAC inhibitors.
- Both quisinostat and romidepsin significantly inhibited tumor growth in vivo.
Conclusions:
- Treatment-naïve, biopsy-derived DMG models are valuable for drug discovery.
- Quisinostat and romidepsin are effective HDAC inhibitors against DMG in vivo.
- Identified potential mechanisms and biomarkers for HDAC inhibitor efficacy in DMG.
- Highlighted the need for brain-penetrant HDAC inhibitors for clinical application.
