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

Cell Rep. 2021 Nov 2;37(5):109957. doi: 10.1016/j.celrep.2021.109957.

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.

Keywords: EGFR signaling; Membrane lipids; SMPD1; combination therapy; electronic medical records; fluoxetine; glioblastoma; real-world evidence; sphingolipid metabolism.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Repositioning*
  • Electronic Health Records
  • Energy Metabolism / drug effects*
  • ErbB Receptors / metabolism
  • Female
  • Fluoxetine / metabolism
  • Fluoxetine / pharmacology*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mice, Nude
  • Permeability
  • Retrospective Studies
  • Signal Transduction / drug effects*
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelins / metabolism
  • Temozolomide / pharmacology
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Sphingomyelins
  • Fluoxetine
  • EGFR protein, human
  • ErbB Receptors
  • SMPD1 protein, human
  • Sphingomyelin Phosphodiesterase
  • Temozolomide