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Updated: Aug 21, 2026
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Abexinostat attenuates temozolomide-resistant glioma stem cells
Balaji Perumalsamy1, Raghupathy Vengoji1, Anand Thiraviyam1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
Background:
Glioblastoma (GBM) is the most common adult primary brain malignancy. Recent studies demonstrate that temozolomide (TMZ) facilitates the persistence of quiescent glioma stem cells (GSCs), which are responsible for GBM recurrence. An ideal therapy should eradicate both proliferating cells and GSCs. Abexinostat (Abx), a histone deacetylase inhibitor, was identified through connectivity mapping to target the specific GBM signature. Here, we demonstrate the anti-proliferative effect of Abx on both differentiated cells and GSCs.
Methods:
Using patient-derived tumor cultures (PDCs) to test Abx in vitro, ATAC-seq identified chromatin accessibility. Single-spheroid and alkaline phosphatase staining assays were used to test stem cell self-renewal. Aldehyde dehydrogenase activity distinguished mesenchymal GSCs. The efficacy of Abx with TMZ was evaluated in GSC-expressing CK9751 PDC and mesenchymal patient-derived xenografts (PDXs).
Results:
In PDCs (CK9495 and CK9751), Abx decreased the DNA repair machinery (RAD51, CHK1, Ku70, and MGMT) and induced apoptosis. Focused ATAC-seq analysis for promoters of DNA repair (RAD51, Ku70, CHK1, and BRCA1) and stemness (CD44, KLF4, c-Myc, and BMI1) revealed Abx decreased chromatin accessibility. Abx decreased stem cell self-renewal and reduced the mesenchymal stem cell signature (CD44, ALDH1A3 expression, and ALDH1 activity) in vitro GBM models. Abx reduced tumor growth and stemness markers in CK9751 PDC and mesenchymal PDXs.
Conclusion:
Abx reduced both DNA repair machinery and GSC markers by decreasing chromatin accessibility. Abx reduced tumor growth and mesenchymal GSCs in vitro and in vivo in GBM PDC and PDX models, supporting Abx's potential to prevent GSC-mediated therapy resistance and improve patient survival.
Insights
Abexinostat (Abx) reduces glioblastoma growth by targeting cancer stem cells and DNA repair mechanisms. This histone deacetylase inhibitor shows promise in overcoming therapy resistance and improving patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) is a common brain tumor where glioma stem cells (GSCs) drive recurrence.
- Temozolomide (TMZ) therapy can leave GSCs resistant.
- Targeting both proliferating cells and GSCs is crucial for effective GBM treatment.
Purpose of the Study:
- To investigate the anti-proliferative effects of Abexinostat (Abx), a histone deacetylase inhibitor, on glioblastoma cells and GSCs.
- To evaluate Abx's potential to overcome therapy resistance mediated by GSCs.
Main Methods:
- Utilized patient-derived tumor cultures (PDCs) and patient-derived xenografts (PDXs) to test Abx efficacy.
- Employed ATAC-seq to analyze chromatin accessibility changes.
- Assessed stem cell self-renewal, aldehyde dehydrogenase activity, and DNA repair machinery markers.
Main Results:
- Abx decreased DNA repair proteins (RAD51, CHK1, Ku70, MGMT) and induced apoptosis in PDCs.
- Abx reduced chromatin accessibility in promoters of DNA repair and stemness genes.
- Abx inhibited GSC self-renewal and reduced mesenchymal GSC markers, decreasing tumor growth in vitro and in vivo.
Conclusions:
- Abexinostat effectively reduces glioblastoma tumor growth and targets mesenchymal GSCs by decreasing chromatin accessibility.
- Abx diminishes DNA repair machinery and GSC markers, suggesting a role in preventing therapy resistance.
- These findings support Abx's potential to improve glioblastoma patient survival by overcoming GSC-mediated resistance.
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