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 Cloughesy; Harley I Kornblum; Oswald Quehenberger; Andrey Rzhetsky; Benjamin F Cravatt; Paul S Mischel

doi:10.1016/j.celrep.2021.109957

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.

Authors

Junfeng Bi¹, Atif Khan², Jun Tang³, Aaron M Armando⁴, Sihan Wu⁵, Wei Zhang⁶, Ryan C Gimple⁷, Alex Reed⁸, Hui Jing⁸, Tomoyuki Koga⁹, Ivy Tsz-Lo Wong³, Yuchao Gu¹⁰, Shunichiro Miki¹¹, Huijun Yang³, Briana Prager⁷, Ellis J Curtis¹², Derek A Wainwright¹³, Frank B Furnari¹⁴, Jeremy N Rich⁷, Timothy F Cloughesy¹⁵, Harley I Kornblum¹⁶, Oswald Quehenberger⁴, Andrey Rzhetsky¹⁷, Benjamin F Cravatt⁸, Paul S Mischel¹⁸

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: jubi@stanford.edu.
² Department of Medicine, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Department of Pharmacology, UCSD School of Medicine, La Jolla, CA, USA.
⁵ 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.
⁶ Department of Medicine, UCSD School of Medicine, La Jolla, CA, USA.
⁷ Division of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
⁹ Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.
¹⁰ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
¹² 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.
¹³ Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁴ 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.
¹⁵ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
¹⁶ 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.
¹⁷ 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.
¹⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: pmischel@stanford.edu.

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
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding