High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity
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<sup>2+</sup>-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.
Authors
- Rebekka Wegmann (ORCID: https://orcid.org/0000-0001-9616-3303)
- Audrey van Drogen
- Patrick G. A. Pedrioli (ORCID: https://orcid.org/0000-0001-6719-9139)
- Zuzanna Lottenbach
- Sven Baumann (ORCID: https://orcid.org/0000-0002-3453-5308)
- Tobias Weiß (ORCID: https://orcid.org/0000-0002-5533-9429)
- Michael Weller (ORCID: https://orcid.org/0000-0002-1748-174X)
- Sohyon Lee (ORCID: https://orcid.org/0000-0003-4790-4990)
- Yasmin Festl
- Anna Maria Zeitlberger (ORCID: https://orcid.org/0000-0002-9837-5534)
- Bartłomiej Augustynek (ORCID: https://orcid.org/0000-0002-4912-2936)
- Flavio Vasella (ORCID: https://orcid.org/0000-0002-8953-0862)
- Sandra Goetze (ORCID: https://orcid.org/0000-0001-6880-8020)
- Marian C. Neidert (ORCID: https://orcid.org/0000-0003-2828-4706)
- Berend Snijder (ORCID: https://orcid.org/0000-0003-3386-6583)
- Michel Bihl (ORCID: https://orcid.org/0000-0002-5884-739X)
- Alicia Buck (ORCID: https://orcid.org/0000-0001-9922-4474)
- Daniel S. Kirschenbaum (ORCID: https://orcid.org/0000-0002-0609-8788)
- David Pentón (ORCID: https://orcid.org/0000-0002-6425-3766)
- Bernd Wollscheid (ORCID: https://orcid.org/0000-0002-3923-1610)
- Julien Mena (ORCID: https://orcid.org/0000-0001-8040-810X)
- Matthias A. Hediger (ORCID: https://orcid.org/0000-0003-1946-027X)
- Elisabeth J. Rushing (ORCID: https://orcid.org/0000-0001-7616-6320)
- Marcel Bühler (ORCID: https://orcid.org/0000-0001-9608-1316)
- Miaomiao Sun
Institutions
- University of Bern (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Zurich (CH)
- Kantonsspital St. Gallen (CH)
- University Hospital of Bern (CH)
- ETH Zurich (CH)
- Institute for Biomedical Engineering (CH)
- University Hospital of Zurich (CH)
Publication Details
- Journal
- Nature Medicine
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1038/s41591-024-03224-y
- Citations
- 58
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 13.56
Funders
- National Science Foundation
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Eidgenössische Technische Hochschule Zürich
- Universität Zürich
- Swiss Cancer Research Foundation
- Helmut Horten Stiftung
- Functional Genomics Center Zurich