Dataset Information

High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity

ABSTRACT: Glioblastoma, the most aggressive primary brain cancer, has dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we here systematically screen repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling >2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of >1 million compounds with high patient validation accuracy. Deep multi-modal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the antidepressant Vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bernd Wollscheid

PROVIDER: MSV000090357 | MassIVE |

REPOSITORIES: MassIVE

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High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity.

Lee Sohyon S Weiss Tobias T Bühler Marcel M Mena Julien J Lottenbach Zuzanna Z Wegmann Rebekka R Sun Miaomiao M Bihl Michel M Augustynek Bartłomiej B Baumann Sven P SP Goetze Sandra S van Drogen Audrey A Pedrioli Patrick G A PGA Penton David D Festl Yasmin Y Buck Alicia A Kirschenbaum Daniel D Zeitlberger Anna M AM Neidert Marian C MC Vasella Flavio F Rushing Elisabeth J EJ Wollscheid Bernd B Hediger Matthias A MA Weller Michael M Snijder Berend B

Nature medicine 20240920 11

Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug response ...[more]

PMID: 39304781

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