PT  - JOURNAL ARTICLE
AU  - Junfeng Bi
AU  - Atif Khan
AU  - Jun Tang
AU  - Sihan Wu
AU  - Wei Zhang
AU  - Ryan C. Gimple
AU  - Tomoyuki Koga
AU  - Aaron M. Armando
AU  - Shunichiro Miki
AU  - Huijun Yang
AU  - Briana Prager
AU  - Ellis J. Curtis
AU  - Derek A. Wainwright
AU  - Frank B. Furnari
AU  - Jeremy N. Rich
AU  - Timothy F. Cloughesy
AU  - Oswald Quehenberger
AU  - Harley I. Kornblum
AU  - Andrey Rzhetsky
AU  - Benjamin F. Cravatt
AU  - Paul S. Mischel
TI  - Targeting Glioblastoma Signaling and Metabolism with A Re-Purposed Brain-Penetrant Drug
AID  - 10.1101/2021.03.16.435487
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.16.435487
4099  - http://biorxiv.org/content/early/2021/03/17/2021.03.16.435487.short
4100  - http://biorxiv.org/content/early/2021/03/17/2021.03.16.435487.full
AB  - The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify SMPD1, an enzyme that regulates the conversion of sphingomyelin to ceramide and a critical regulator of plasma membrane structure and organization, as an actionable drug target in glioblastoma. We show that the safe and highly brain-penetrant antidepressant fluoxetine, potently inhibits SMPD1 activity, killing GBMs, in vitro and in patient-derived xenografts, through inhibition of EGFR signaling and via activation of lysosomal stress. Combining fluoxetine with the chemotherapeutic agent temozolomide, a standard of care for GBM patients, causes massive increases in GBM cell death, and complete and long-lived tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases, reveals significantly increased survival in glioblastoma patients treated with fluoxetine, which was not seen in patients treated with other SSRI anti-depressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for GBM patients and suggest prospective randomized clinical trials.Competing Interest StatementP.S.M. is co-founder of Boundless Bio, Inc. He has equity in the company, chairs the scientific advisory board, and serves as a consultant, for which he is compensated.