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Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
Bi, Junfeng; Khan, Atif; Tang, Jun; Armando, Aaron M; Wu, Sihan; Zhang, Wei; Gimple, Ryan C; Reed, Alex; Jing, Hui; Koga, Tomoyuki; Wong, Ivy Tsz-Lo; Gu, Yuchao; Miki, Shunichiro; Yang, Huijun; Prager, Briana; Curtis, Ellis J; Wainwright, Derek A; Furnari, Frank B; Rich, Jeremy N; Cloughesy, Timothy F; Kornblum, Harley I; Quehenberger, Oswald; Rzhetsky, Andrey; Cravatt, Benjamin F; Mischel, Paul S.
Affiliation
  • Bi J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: jubi@stanford.edu.
  • Khan A; Department of Medicine, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
  • Tang J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
  • Armando AM; Department of Pharmacology, UCSD School of Medicine, La Jolla, CA, USA.
  • Wu S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Zhang W; Department of Medicine, UCSD School of Medicine, La Jolla, CA, USA.
  • Gimple RC; Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • Reed A; Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • Jing H; Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • Koga T; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.
  • Wong IT; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
  • Gu Y; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Miki S; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
  • Yang H; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
  • Prager B; Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • Curtis EJ; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA, USA.
  • Wainwright DA; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Furnari FB; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA, USA.
  • Rich JN; Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • Cloughesy TF; Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
  • Kornblum HI; Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, CA, USA.
  • Quehenberger O; Department of Pharmacology, UCSD School of Medicine, La Jolla, CA, USA.
  • Rzhetsky A; Department of Medicine, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA; Department of Human Genetics, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
  • Cravatt BF; Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • Mischel PS; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: pmischel@stanford.edu.
Cell Rep ; 37(5): 109957, 2021 11 02.
Article in En | MEDLINE | ID: mdl-34731610
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Blood-Brain Barrier / Signal Transduction / Fluoxetine / Glioblastoma / Energy Metabolism / Drug Repositioning / Antineoplastic Agents Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Cell Rep Year: 2021 Document type: Article Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Blood-Brain Barrier / Signal Transduction / Fluoxetine / Glioblastoma / Energy Metabolism / Drug Repositioning / Antineoplastic Agents Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans Language: En Journal: Cell Rep Year: 2021 Document type: Article Country of publication: United States