Retrospective analysis of the impact of acid sphingomyelinase inhibiting drugs on survival of patients with glioblastoma

Retrospective analysis of the impact of acid sphingomyelinase inhibiting drugs on survival of patients with glioblastoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retrospective analysis of the impact of acid sphingomyelinase inhibiting drugs on survival of patients with glioblastoma Cindy M. Liu, Luiz Henrique Medeiros Geraldo, Julie Xiao, Erik P. Sulman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8022772/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jan, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted 18 You are reading this latest preprint version Abstract Purpose Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and remains difficult to treat. Though still under investigation, acid sphingomyelinase (ASM) has been implicated in GBM lipid raft formation, which facilitates cancer signaling. We sought to verify if, and if so what kinds of ASM inhibitors (ASMis) improve outcomes in GBM. Methods We conducted a retrospective study of GBM patients treated between 2002 and 2024 at one academic center. ASMi impact on overall survival (OS) was assessed using Kaplan-Meier analysis and Cox proportional hazards models adjusting for age, sex, tumor location, use of tumor-treating fields (TTFs), and MGMT promoter methylation status. Propensity score matching was performed to account for baseline imbalances. Results ASMi use alone was not associated with a statistically significant OS benefit (HR = 0.80, 95% CI 0.55–1.2, p = 0.247). Stratifying by ASMi revealed fluoxetine as the only medication that significantly improved OS (HR = 0.35, 95% CI 0.14–0.88, p = 0.025). In a fluoxetine-only multivariate analysis (n = 20 vs. 186 controls), the survival benefit remained significant (HR = 0.29, 95% CI 0.11–0.73, p = 0.009). This effect persisted in the propensity-matched cohort (HR = 0.24, 95% CI 0.066–0.89, p = 0.033). Age and unmethylated MGMT promoter status were associated with decreased survival across multiple analyses. Conclusion Fluoxetine was independently associated with increased survival in GBM patients whereas ASMi use overall was not. These findings suggest that fluoxetine may have unique anti-tumor effects beyond ASM inhibition and justify further investigation. Glioblastoma fluoxetine acid sphingomyelinase inhibitior Full Text Additional Declarations Competing interest reported. Erik P. Sulman received institutional research funding from Novocure. Cite Share Download PDF Status: Published Journal Publication published 03 Jan, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 24 Nov, 2025 Reviews received at journal 20 Nov, 2025 Reviews received at journal 19 Nov, 2025 Reviews received at journal 19 Nov, 2025 Reviews received at journal 18 Nov, 2025 Reviews received at journal 17 Nov, 2025 Reviewers agreed at journal 14 Nov, 2025 Reviewers agreed at journal 12 Nov, 2025 Reviewers agreed at journal 11 Nov, 2025 Reviewers agreed at journal 10 Nov, 2025 Reviewers agreed at journal 10 Nov, 2025 Reviews received at journal 08 Nov, 2025 Reviewers agreed at journal 08 Nov, 2025 Reviewers agreed at journal 06 Nov, 2025 Reviewers invited by journal 06 Nov, 2025 Editor assigned by journal 06 Nov, 2025 Submission checks completed at journal 06 Nov, 2025 First submitted to journal 03 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8022772","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":545763584,"identity":"4a35afc8-1b24-4abd-9ce3-b7a18750770f","order_by":0,"name":"Cindy M. 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Erik P. Sulman received institutional research funding from Novocure.","formattedTitle":"Retrospective analysis of the impact of acid sphingomyelinase inhibiting drugs on survival of patients with glioblastoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Glioblastoma, fluoxetine, acid sphingomyelinase inhibitior","lastPublishedDoi":"10.21203/rs.3.rs-8022772/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8022772/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eGlioblastoma (GBM) is the most common malignant primary brain tumor in adults and remains difficult to treat. Though still under investigation, acid sphingomyelinase (ASM) has been implicated in GBM lipid raft formation, which facilitates cancer signaling. We sought to verify if, and if so what kinds of ASM inhibitors (ASMis) improve outcomes in GBM.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective study of GBM patients treated between 2002 and 2024 at one academic center. ASMi impact on overall survival (OS) was assessed using Kaplan-Meier analysis and Cox proportional hazards models adjusting for age, sex, tumor location, use of tumor-treating fields (TTFs), and MGMT promoter methylation status. Propensity score matching was performed to account for baseline imbalances.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eASMi use alone was not associated with a statistically significant OS benefit (HR\u0026thinsp;=\u0026thinsp;0.80, 95% CI 0.55\u0026ndash;1.2, p\u0026thinsp;=\u0026thinsp;0.247). Stratifying by ASMi revealed fluoxetine as the only medication that significantly improved OS (HR\u0026thinsp;=\u0026thinsp;0.35, 95% CI 0.14\u0026ndash;0.88, p\u0026thinsp;=\u0026thinsp;0.025). In a fluoxetine-only multivariate analysis (n\u0026thinsp;=\u0026thinsp;20 vs. 186 controls), the survival benefit remained significant (HR\u0026thinsp;=\u0026thinsp;0.29, 95% CI 0.11\u0026ndash;0.73, p\u0026thinsp;=\u0026thinsp;0.009). This effect persisted in the propensity-matched cohort (HR\u0026thinsp;=\u0026thinsp;0.24, 95% CI 0.066\u0026ndash;0.89, p\u0026thinsp;=\u0026thinsp;0.033). Age and unmethylated MGMT promoter status were associated with decreased survival across multiple analyses.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eFluoxetine was independently associated with increased survival in GBM patients whereas ASMi use overall was not. These findings suggest that fluoxetine may have unique anti-tumor effects beyond ASM inhibition and justify further investigation.\u003c/p\u003e","manuscriptTitle":"Retrospective analysis of the impact of acid sphingomyelinase inhibiting drugs on survival of patients with glioblastoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 15:20:03","doi":"10.21203/rs.3.rs-8022772/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-24T11:20:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T01:03:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T03:00:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T22:39:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-18T10:28:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-18T01:52:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"152709574326239190054808214758718094","date":"2025-11-14T12:08:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"127999300984449132204311368247729477938","date":"2025-11-12T17:56:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14287887515916882801727064281209316131","date":"2025-11-11T13:13:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54557830105763240621164158992741508548","date":"2025-11-10T15:13:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"311668180923483359790096776882667496906","date":"2025-11-10T13:10:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-08T22:16:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279845496762070835539313331860641150868","date":"2025-11-08T12:36:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86713784622136926293995627414795324011","date":"2025-11-06T14:17:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-06T11:37:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-06T09:11:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-06T09:06:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-11-03T22:15:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9be7d0a0-ed8c-4616-807a-da17055b9684","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T15:59:18+00:00","versionOfRecord":{"articleIdentity":"rs-8022772","link":"https://doi.org/10.1007/s11060-025-05388-0","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2026-01-03 15:57:08","publishedOnDateReadable":"January 3rd, 2026"},"versionCreatedAt":"2025-11-17 15:20:03","video":"","vorDoi":"10.1007/s11060-025-05388-0","vorDoiUrl":"https://doi.org/10.1007/s11060-025-05388-0","workflowStages":[]},"version":"v1","identity":"rs-8022772","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8022772","identity":"rs-8022772","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}