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

15 Scopus citations

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

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute for Neurological Diseases and Stroke (NS73831 and NS080939), the Defeat GBM Program of the National Brain Tumor Society, the Ben and Catherine Ivy Foundation, an award from the Sharpe/National Brain Tumor Society Research Program, a Compute for the Cure Award from the Nvidia Foundation (P.S.M.), and a UCSD Neuroscience Microscopy Shared Facility Grant (P30 NS047101). P.S.M. dedicates this paper to Bob Sharpe, a friend and remarkable person who, during his battle with GBM, courageously and gracefully taught him so much about living. J.B. and P.S.M conceived the study and designed all experiments. J.B. J.T. I.T.-L.W. A.R. H.J. Y.G. and H.Y. performed experiments. A.K. and A.R. analyzed patient datasets from electronic medical records. J.B. S.W. W.Z. R.C.G. and B.P. performed the bioinformatics analysis. J.B. J.T. T.K. S.M. and E.J.C. contributed to the mouse experiments. A.M.A. and O.Q. performed the lipidomics analysis. H.I.K. and F.B.F. provided cell lines or regents and intellectual input. D.A.W. T.F.C. J.N.R. and B.F.C. provided intellectual input. J.B. W.Z. A.M.A. O.Q. B.F.C. and P.S.M. analyzed and interpreted data. J.B. and P.S.M. wrote the manuscript, and all authors edited and approved the manuscript. P.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. P.S.M. is also consultant for Autobahn Therapeutics, Inc. and Sage Therapeutics. These consulting arrangements started after completion of this paper.

Funding Information:
This work was supported by grants from the National Institute for Neurological Diseases and Stroke ( NS73831 and NS080939 ), the Defeat GBM Program of the National Brain Tumor Society , the Ben and Catherine Ivy Foundation , an award from the Sharpe/National Brain Tumor Society Research Program , a Compute for the Cure Award from the Nvidia Foundation (P.S.M.), and a UCSD Neuroscience Microscopy Shared Facility Grant ( P30 NS047101 ). P.S.M. dedicates this paper to Bob Sharpe, a friend and remarkable person who, during his battle with GBM, courageously and gracefully taught him so much about living.

Publisher Copyright:
© 2021 The Author(s)

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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