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Updated: Nov 23, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Data-driven prioritization and preclinical evaluation of therapeutic targets in glioblastoma
Cyrillo G Brahm1,2, U Kulsoom Abdul3, Megan Houweling3
1Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Background:
Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM.
Methods:
mRNA expression data of patient-derived GBM (n = 1279) and normal brain tissue (n = 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo.
Results:
We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including EGFR and VEGFA, have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes, RRM2, MAPK9 (JNK2, SAPK1a), and XIAP play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth.
Conclusions:
The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
Insights
Researchers identified new therapeutic targets for glioblastoma (GBM) by analyzing gene expression. A MAPK9 inhibitor, RGB-286638, showed promise in lab studies for treating this aggressive brain cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Glioblastoma (GBM) presents a significant clinical challenge with limited therapeutic options.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To identify novel therapeutic targets for glioblastoma (GBM).
- To prioritize and validate potential drug candidates against these targets.
Main Methods:
- Utilized mRNA expression data from 1279 GBM and 46 normal brain samples.
- Applied functional genomic profiling and class comparison to identify upregulated genes in GBM.
- Prioritized genes based on drug interactions, clinical development status, and pathway association.
Main Results:
- Identified 712 significantly upregulated genes in GBM; 27 interact with antineoplastic agents.
- Highlighted RRM2, MAPK9, and XIAP as key genes in GBM development.
- Demonstrated that the MAPK9 inhibitor RGB-286638 reduced GBM cell viability in vitro and showed potential for delaying tumor growth in vivo.
Conclusions:
- The MAPK9 inhibitor RGB-286638 exhibits promising in vitro efficacy against glioblastoma.
- Further in vivo studies, including target engagement and combination therapies, are warranted for RGB-286638.
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