Targeting Glioblastoma Signaling and Metabolism with A Re-Purposed Brain-Penetrant Drug
By
Junfeng Bi,
Atif Khan,
Jun Tang,
Sihan Wu,
Wei Zhang,
Ryan C. Gimple,
Tomoyuki Koga,
Aaron M. Armando,
Shunichiro Miki,
Huijun Yang,
Briana Prager,
Ellis J. Curtis,
Derek A. Wainwright,
Frank B. Furnari,
Jeremy N Rich,
Timothy F Cloughesy,
Oswald Quehenberger,
Harley I Kornblum,
Andrey Rzhetsky,
Benjamin F Cravatt,
Paul S Mischel
Posted 17 Mar 2021
bioRxiv DOI: 10.1101/2021.03.16.435487
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.
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