Lee, SohyonSohyonLeeWeiss, TobiasTobiasWeissBühler, MarcelMarcelBühler0000-0001-6433-6257Mena, JulienJulienMenaLottenbach, ZuzannaZuzannaLottenbachWegmann, RebekkaRebekkaWegmannSun, MiaomiaoMiaomiaoSunBihl, MichelMichelBihlAugustynek, Bartlomiej StanislawBartlomiej StanislawAugustynekBaumann, Sven PatricSven PatricBaumannGoetze, SandraSandraGoetzevan Drogen, AudreyAudreyvan DrogenPedrioli, Patrick G APatrick G APedrioliPenton, DavidDavidPentonFestl, YasminYasminFestlBuck, AliciaAliciaBuckKirschenbaum, DanielDanielKirschenbaumZeitlberger, Anna MAnna MZeitlbergerNeidert, Marian CMarian CNeidertVasella, FlavioFlavioVasellaRushing, Elisabeth JElisabeth JRushingWollscheid, BerndBerndWollscheidHediger, MatthiasMatthiasHediger0000-0003-1946-027XWeller, MichaelMichaelWellerSnijder, BerendBerendSnijder2024-10-292024-10-292024-11https://boris-portal.unibe.ch/handle/20.500.12422/125342Glioblastoma, 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 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 more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.en600 - Technology::610 - Medicine & healtharticle10.48620/749003930478110.1038/s41591-024-03224-y