Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug
Summary: 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 con...
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Elsevier
2021
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oai:doaj.org-article:8516b7196aa84c49af33aefb9f94a1032021-11-04T04:29:53ZTargeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug2211-124710.1016/j.celrep.2021.109957https://doaj.org/article/8516b7196aa84c49af33aefb9f94a1032021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014340https://doaj.org/toc/2211-1247Summary: 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.Junfeng BiAtif KhanJun TangAaron M. ArmandoSihan WuWei ZhangRyan C. GimpleAlex ReedHui JingTomoyuki KogaIvy Tsz-Lo WongYuchao GuShunichiro MikiHuijun YangBriana PragerEllis J. CurtisDerek A. WainwrightFrank B. FurnariJeremy N. RichTimothy F. CloughesyHarley I. KornblumOswald QuehenbergerAndrey RzhetskyBenjamin F. CravattPaul S. MischelElsevierarticleglioblastomasphingolipid metabolismSMPD1fluoxetineMembrane lipidsEGFR signalingBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 5, Pp 109957- (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
glioblastoma sphingolipid metabolism SMPD1 fluoxetine Membrane lipids EGFR signaling Biology (General) QH301-705.5 |
| spellingShingle |
glioblastoma sphingolipid metabolism SMPD1 fluoxetine Membrane lipids EGFR signaling Biology (General) QH301-705.5 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 Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| description |
Summary: 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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Junfeng Bi |
| title |
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| title_short |
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| title_full |
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| title_fullStr |
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| title_full_unstemmed |
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| title_sort |
targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/8516b7196aa84c49af33aefb9f94a103 |
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