Abstract

Abstract There remains an unmet need for novel treatment strategies against glioblastoma that are more effective than the current standard of care. However, the complex tumor microenvironment and genetic heterogeneity of these tumors require novel technologies enabling high-throughput assessment of cellular responses to treatments on a functional level in complex tumor samples with an intact cellular microenvironment. Here, we used a novel single-cell functional tissue profiling platform based on high—throughput microscopy followed by computer vision and machine learning algorithms to screen 70 clinically-approved drugs with good blood-brain-barrier penetration in 35 glioblastoma patient samples that were freshly obtained from surgery. This revealed prognostically relevant subtypes of glioma cell morphologies and promising candidates for drug repurposing. Among the drugs with potent anti-glioma activity, we identified the antidepressant Vortioxetine, that had strong anti-glioma activity across patients independent of the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT). Complementrary in vitro studies using patient-derived glioma cell lines and orthotopic glioma xenograft mouse models confirmed the strong anti-glioma activity of Vortioxetine, leading to a notable fraction of long-term surviving mice. Mechanistically, multiplexed transcriptomics and proteomics unveiled that Vortioxetine induced an upregulation of the Activator protein 1 (AP-1) transcription factor family, along with the B-cell translocation gene (BTG) tumor suppressor genes. These findings serve as the cornerstone for future clinical applications of the single-cell functional tissue profiling platform and the potential clinical translation of Vortioxetine as a promising drug-repurposing candidate for glioblastoma patients.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call