Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug

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 sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials. [Display omitted] •The unique membrane lipid composition makes GBMs sensitive to SMPD1 inhibition•Fluoxetine inhibits SMPD1, sphingomyelin metabolism, and EGFR signaling in GBM•Fluoxetine safely and potently shrinks GBM tumors and prevents recurrence in mice•Addition of fluoxetine to standard-of-care chemotherapy improves patient survival Bi et al. reveal an actionable lipid vulnerability in GBM that can be exploited with a safe, highly brain-penetrant, FDA-approved drug. They show that fluoxetine kills GBMs by blocking acid sphingomyelinase, and they demonstrate that, when added to standard of care, fluoxetine, unlike other SSRIs, significantly improves patient survival.