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

Junfeng Bi, Atif Khan, Jun Tang, Aaron M. Armando, Sihan Wu, Wei Zhang, Ryan C. Gimple, Alex Reed, Hui Jing, Tomoyuki Koga, Ivy Tsz Lo Wong, Yuchao Gu, Shunichiro Miki, Huijun Yang, Briana Prager, Ellis J. Curtis, Derek A. Wainwright, Frank B. Furnari, Jeremy N. Rich, Timothy F. CloughesyHarley I. Kornblum, Oswald Quehenberger, Andrey Rzhetsky, Benjamin F. Cravatt, Paul S. Mischel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number109957
JournalCell Reports
Volume37
Issue number5
DOIs
StatePublished - Nov 2 2021

Keywords

  • EGFR signaling
  • Membrane lipids
  • SMPD1
  • combination therapy
  • electronic medical records
  • fluoxetine
  • glioblastoma
  • real-world evidence
  • sphingolipid metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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