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ETH Zurich, 현 KAIST 생명과학과

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Nat. Med., Sep 20 2024, | https://doi.org/10.1038/s41591-024-03224-y High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity

Sohyon Lee ^1,14, Tobias Weiss ^2,14, Marcel Bühler ², Julien Mena ¹, Zuzanna Lottenbach ¹, Rebekka Wegmann ¹, Miaomiao Sun ², Michel Bihl ³, Bartłomiej Augustynek ^4,5, Sven P. Baumann⁴, Sandra Goetze ^6,7,8, Audrey van Drogen^6,7,8, Patrick G. A. Pedrioli ^6,7,8, David Penton ⁹, Yasmin Festl ¹, Alicia Buck ^1,2, Daniel Kirschenbaum ¹⁰, Anna M. Zeitlberger ¹¹, Marian C. Neidert ¹¹, Flavio Vasella ¹², Elisabeth J. Rushing ¹⁰, Bernd Wollscheid ^6,7,8, Matthias A. Hediger ⁴, Michael Weller ^2,13,15 & Berend Snijder ^1,7,13,15,*

¹Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
²Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
³Institute of Pathology, University Hospital Zurich, Zurich, Switzerland.
⁴Membrane Transport Discovery Lab, Department of Nephrology and Hypertension and Department of Biomedical Research, Inselspital, University of Bern, Bern, Switzerland.
⁵Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
⁶Department of Health Sciences and Technology, Institute of Translational Medicine (ITM), ETH Zurich, Zurich, Switzerland.
⁷Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁸ETH PHRT Swiss Multi-Omics Center (SMOC), Zurich, Switzerland.
⁹Electrophysiology Facility, University of Zurich, Zurich, Switzerland.
¹⁰Department of Neuropathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹¹Department of Neurosurgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
¹²Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
¹³Comprehensive Cancer Center Zurich, University Hospital Zurich, Zurich, Switzerland.
¹⁴These authors contributed equally: Sohyon Lee, Tobias Weiss.
¹⁵These authors jointly supervised this work: Michael Weller, Berend Snijder.

^*Corresponding author: correspondence to Berend Snijder

Abstract

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 Ca²⁺-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.

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형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-30)
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