Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain cancer characterized by highly invasive growth driven by glial-mesenchymal transition (GMT). Given the urgent need for effective therapies targeting this process, we aimed to discover potential GMT inhibitors using transcriptomic-based repurposing applied to both approved and experimental drugs. Deep bioinformatic analysis of transcriptomic data from GBM patient tumors and GBM cell lines with mesenchymal phenotype using gene set variation analysis (GSVA), weighted gene co-expression network analysis (WGCNA), reconstruction of GMT-related gene association networks, gene set enrichment analysis (GSEA), and the search for correlation with transcriptomic profiles of known GMT markers, revealed a novel 31-gene GMT signature applicable as relevant input data for the connectivity map-based drug repurposing study. Using this gene signature, a number of small-molecule compounds were predicted as potent anti-GMT agents. Further ranking according to their blood-brain barrier permeability, as well as structural and transcriptomic similarities to known anti-GBM drugs, revealed SP600125, vemurafenib, FG-7142, dibenzoylmethane, and phensuximide as the most promising for GMT inhibition. In vitro validation showed that SP600125, which is most closely associated with GMT-related hub genes, effectively inhibited TGF-β1- and chemical hypoxia-induced GMT in U87 GBM cells by reducing morphological changes, migration, vasculogenic mimicry, and mesenchymal marker expression. These results clearly demonstrate the applicability of connectivity mapping as a powerful tool to accelerate the discovery of effective GMT-targeting therapies for GBM and significantly expand our understanding of the antitumor potential of SP600125.