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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Dissecting the Dual Drug Candidates Against Glioblastoma and Oligodendroglioma Through Integrated Transcriptome
Tuba Sevimoglu1, Zihni Onur Çalışkaner2
1Department of Bioengineering, University of Health Sciences, Istanbul, Türkiye. tuba.sevimoglu@sbu.edu.tr.
Abstract:
Cancer is one of the prominent causes of death, and brain cancer accounts for about 2% of this figure, with glioma being the major type. This study aims to identify biomarker candidates for glioma subtypes, specifically glioblastoma (GBM) and oligodendroglioma (ODG), as well as to disclose repurposed drug candidates common to these brain tumors. Gene expression profiles were analyzed and integrated with data from proteomics interactions as well as miRNA regulation. 23 mutual core DEGs (differentially expressed genes) were identified. Correlation networks and protein interaction networks were constructed from these core DEGs. Hubs of the protein interaction networks (CALM1), miRNA - core DEG interaction network (SOX4, MTHFD2, and CALM1), and correlation networks such as ABCA2, TPPP, PPP1R16B, SPOCK3, and SPARC, as well as central miRNAs (hsa-miR-1-3p, hsa-miR-19b-3p, and hsa-miR-335-5p) were identified. Furthermore, candidate therapeutic agents were revealed. Docking-based virtual screening suggests that budesonide, sirolimus, cephaeline, etoposide, and staurosporine may target proteins upregulated in GBM and ODG, such as APOC, MTHFD2, and LPL, in addition to their actual targets. Particularly, sirolimus and protriptyline exhibited comparable binding affinities against MTHFD2 (-11.23 kcal/mol) and LPL (-7.45 kcal/mol), respectively, compared to their actual targets. The holistic network-based approach applied in this study may be advantageous in the illumination of these subtypes and may aid in the design of improved therapeutics in treatment of the studied gliomas.
Insights
This study identifies key biomarkers and repurposed drugs for brain gliomas, including glioblastoma and oligodendroglioma. Network analysis revealed potential therapeutic agents like sirolimus and protriptyline for these aggressive brain tumors.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Glioma, a major brain tumor type, necessitates novel therapeutic strategies.
- Glioblastoma (GBM) and oligodendroglioma (ODG) are distinct glioma subtypes with unique molecular profiles.
- Identifying shared biomarkers and drug targets can advance treatment for these brain cancers.
Purpose of the Study:
- To identify potential biomarker candidates for glioblastoma (GBM) and oligodendroglioma (ODG) subtypes.
- To discover repurposed drug candidates common to these brain tumors.
- To elucidate molecular mechanisms through integrated network analysis.
Main Methods:
- Analysis of gene expression profiles integrated with proteomics and miRNA regulation data.
- Construction of correlation and protein-protein interaction networks from differentially expressed genes (DEGs).
- Docking-based virtual screening for drug repurposing and target identification.
Main Results:
- Identification of 23 mutual core DEGs and key network hubs (e.g., CALM1, SOX4, MTHFD2).
- Discovery of central miRNAs (hsa-miR-1-3p, hsa-miR-19b-3p, hsa-miR-335-5p) associated with glioma subtypes.
- Virtual screening suggested repurposed drugs (budesonide, sirolimus, etoposide) targeting upregulated proteins (MTHFD2, LPL) in GBM and ODG.
Conclusions:
- A network-based approach effectively identified potential biomarkers and drug candidates for glioma subtypes.
- Sirolimus and protriptyline show promising binding affinities for MTHFD2 and LPL, respectively.
- This study provides a foundation for developing improved therapeutics for glioblastoma and oligodendroglioma.
