Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification.
Aideen C RoddyCaitríona E McInerneyTom FlanneryEstelle G HealyJames P StewartVeronica J SpenceJamie WalshManuel Salto-TellezDarragh G McArtKevin M PrisePublished in: Biomedicines (2023)
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.
Keyphrases
- stem cells
- single cell
- case report
- genome wide
- genome wide identification
- gene expression
- free survival
- end stage renal disease
- transcription factor
- healthcare
- ejection fraction
- high resolution
- systematic review
- endothelial cells
- rna seq
- poor prognosis
- signaling pathway
- small molecule
- mental health
- chronic kidney disease
- low grade
- binding protein
- adverse drug
- peritoneal dialysis
- mass spectrometry
- mesenchymal stem cells
- fluorescence imaging
- oxidative stress
- drug induced
- long non coding rna
- fluorescent probe
- living cells
- big data
- smoking cessation
- resting state