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Updated: Nov 9, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma
Miguel Jiménez-Alcázar1, Álvaro Curiel-García1, Paula Nogales1
1Seve Ballesteros Foundation-Brain Tumors Group, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Abstract:
Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance in vitro Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G2-M phase, independently of MGMT or MMR status, thus circumventing conventional resistance mechanisms to TMZ. Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells in vitro, ex vivo, and in vivo We propose this combinatorial treatment as a potential approach for patients with GBM.
Insights
Dianhydrogalactitol (Val-083) overcomes temozolomide (TMZ) resistance in glioblastoma (GBM) by inducing DNA damage independently of MGMT or MMR status. Combining Val-083 with TMZ shows synergistic effects, offering a novel therapeutic strategy for GBM patients.
Area of Science:
- Neuro-oncology
- Cancer biology
- Chemotherapy resistance mechanisms
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- Chemotherapy resistance, particularly to temozolomide (TMZ), is a major challenge in GBM treatment.
- Understanding resistance mechanisms is crucial for developing effective therapies.
Purpose of the Study:
- To identify drivers of TMZ resistance in GBM.
- To evaluate dianhydrogalactitol (Val-083) as a treatment to overcome TMZ resistance.
- To assess the efficacy of combining Val-083 with TMZ.
Main Methods:
- shRNA screening in GBM cell lines with varying O6-methylguanine-DNA methyl-transferase (MGMT) expression.
- In vitro, ex vivo, and in vivo studies of Val-083 treatment on GBM cells and tumors.
- Assessment of DNA damage, cell-cycle arrest, and synergistic cytotoxicity.
Main Results:
- Loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms of TMZ resistance.
- Val-083 induces DNA damage and G2-M cell-cycle arrest in GBM cells, irrespective of MGMT or MMR status.
- Combination therapy with TMZ and Val-083 demonstrated synergistic cytotoxicity across multiple models.
Conclusions:
- Val-083 circumvents common TMZ resistance mechanisms in GBM.
- Combined TMZ and Val-083 therapy presents a promising strategy for treating GBM.
- This combinatorial approach warrants further investigation for clinical application in GBM patients.
