High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity.
Publication Date: 2024 Nov
Full Text Sources
Authors
Sohyon Lee; Tobias Weiss; Marcel Bühler; Julien Mena; Zuzanna Lottenbach; Rebekka Wegmann; Miaomiao Sun; Michel Bihl; Bartłomiej Augustynek; Sven P Baumann; Sandra Goetze; Audrey van Drogen; Patrick G A Pedrioli; David Penton; Yasmin Festl; Alicia Buck; Daniel Kirschenbaum; Anna M Zeitlberger; Marian C Neidert; Flavio Vasella; Elisabeth J Rushing; Bernd Wollscheid; Matthias A Hediger; Michael Weller; Berend SnijderAbstract
OBJECTIVE
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 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.
Source
Nature medicine
Pub Types(s)
Journal Article
Language
English
PubMed ID
39304781