1. Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug
- Author
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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, and Mischel, Paul S
- Subjects
Biological Sciences ,Cancer ,Brain Cancer ,Mental Health ,Brain Disorders ,Rare Diseases ,Neurosciences ,Depression ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Animals ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Blood-Brain Barrier ,Brain Neoplasms ,Cell Line ,Tumor ,Drug Repositioning ,Electronic Health Records ,Energy Metabolism ,ErbB Receptors ,Female ,Fluoxetine ,Glioblastoma ,Humans ,Mice ,Nude ,Permeability ,Retrospective Studies ,Signal Transduction ,Sphingomyelin Phosphodiesterase ,Sphingomyelins ,Temozolomide ,Tumor Burden ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,EGFR signaling ,Membrane lipids ,SMPD1 ,combination therapy ,electronic medical records ,fluoxetine ,glioblastoma ,real-world evidence ,sphingolipid metabolism ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - 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.
- Published
- 2021