Evidence map›Paper›PMID 34731610›Full record

ArticleCell reports2021

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 and 15 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
83citing papers in PubMed, 2 pooled it
5.4field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

83 citing papers in PubMed, 2 syntheses or guidelines pooled it, 101 citations in OpenAlex.

  1. Pooled it
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  9. The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.Journal of cellular and molecular medicine · 2026
    Review
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23 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors at 9 institutions in 2 countries.

Junfeng BiDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: jubi@stanford.edu.
Atif KhanDepartment of Medicine, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
Jun TangDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
Aaron M ArmandoDepartment of Pharmacology, UCSD School of Medicine, La Jolla, CA, USA.
Sihan WuDepartment 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.
Wei ZhangDepartment of Medicine, UCSD School of Medicine, La Jolla, CA, USA.
Ryan C GimpleDivision of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Alex ReedDepartment of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
Hui JingDepartment of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
Tomoyuki KogaLudwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.
Ivy Tsz-Lo WongDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
Yuchao GuStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Shunichiro MikiLudwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
Huijun YangDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
Briana PragerDivision of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Ellis J CurtisDepartment 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.
Derek A WainwrightDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Frank B FurnariLudwig 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.
Jeremy N RichDivision of Regenerative Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Timothy F CloughesyDepartment of Neurology, David Geffen School of Medicine, University of California Los Angeles, CA, USA.
Harley I KornblumDepartment 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.
Oswald QuehenbergerDepartment of Pharmacology, UCSD School of Medicine, La Jolla, CA, USA.
Andrey RzhetskyDepartment 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.
Benjamin F CravattDepartment of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
Paul S MischelDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: pmischel@stanford.edu.
University of California San Diego · USStanford University · USScripps Research Institute · USUniversity of California, Los Angeles · USUniversity of Chicago · USChildren's Medical Center · USNorthwestern University · USStanford Medicine · USUniversity of Minnesota · US

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007250 · NIGMS · CASE WESTERN RESERVE UNIVERSITY · PI HUANG, ALEX YEE-CHEN · 1985 to 2023
$33.4M
UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David A. Nathanson · 2017 to 2026
$25.2M
Stem CellsP30HD004612 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CEPEDA, CARLOS T · 1985 to 2014
$19.5M
UCLA IDDRC: Translational CoreP50HD103557 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Peyman Golshani, SUMA JACOB · 2020 to 2026
$9.6M
U of Calif, San Diego Neuroscience Microscopy ImagingP30NS047101 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G, ZHENG, BINHAI · 2003 to 2022
$9.0M
IDO1 and Immunotolerance in GlioblastomaR01NS097851 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI SCHILTZ, GARY E, WAINWRIGHT, DEREK ALAN · 2016 to 2025
$4.6M
Genotypic Interactions in Brain Cancer HeterogeneityR01NS080939 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FURNARI, FRANK · 2012 to 2022
$3.5M
The role of mTORC2 in reprogramming cancer cell metabolismR01NS073831 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MISCHEL, PAUL S · 2011 to 2020
$3.4M
Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.R01CA238249 · NCI · STANFORD UNIVERSITY · PI CRAVATT, BENJAMIN F, MISCHEL, PAUL S · 2021 to 2025
$3.3M
The interaction of IDO and Tregs Leads to Immunosuppression in GliomaR00NS082381 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI WAINWRIGHT, DEREK ALAN · 2014 to 2016
$735k
Aging, immunosenescence and glioblastomaK02AG068617 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI WAINWRIGHT, DEREK ALAN · 2020 to 2024
$688k
Genotypic Interactions in Brain Cancer HeterogeneityR56NS080939 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FURNARI, FRANK · 2023 to 2023
$537k
NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA238249NIA NIH HHS K02 AG068617NICHD NIH HHS P30 HD004612NICHD NIH HHS P50 HD103557NIGMS NIH HHS T32 GM007250NINDS NIH HHS F32 NS073366NINDS NIH HHS K99 NS082381NINDS NIH HHS P30 NS047101NINDS NIH HHS R00 NS082381NINDS NIH HHS R01 NS073831NINDS NIH HHS R01 NS080939NINDS NIH HHS R56 NS080939
6 · The paper itself

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.

Indexed as

Drug RepositioningAnimalsAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBlood-Brain BarrierBrain NeoplasmsCell Line, TumorElectronic Health RecordsEnergy MetabolismErbB ReceptorsFemaleFluoxetineGlioblastomaHumansMiceMice, NudeAntineoplastic AgentsEGFR protein, humanErbB ReceptorsFluoxetineSMPD1 protein, humanSphingomyelin PhosphodiesteraseSphingomyelinsTemozolomidecombination therapyEGFR signalingelectronic medical recordsfluoxetineglioblastomaMembrane lipidsreal-world evidenceSMPD1sphingolipid metabolism

Identifiers

PMID34731610
PMCPMC8856626
OpenAlexW3209040261

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.