Targeting Glioblastoma Signaling and Metabolism with A Re-Purposed Brain-Penetrant Drug
Ryan C. Gimple,
Aaron M. Armando,
Ellis J. Curtis,
Derek A. Wainwright,
Frank B. Furnari,
Jeremy N Rich,
Timothy F Cloughesy,
Harley I Kornblum,
Benjamin F Cravatt,
Paul S Mischel
Posted 17 Mar 2021
bioRxiv DOI: 10.1101/2021.03.16.435487
Posted 17 Mar 2021
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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