Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma

Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma | 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 Article Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma Jiyang Yu, jingjing liu, Xu Yang, Mingrui Zhu, Xinran Dong, Honglei Zhou, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8278592/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Effective therapies for high-risk medulloblastoma (MB), particularly MYC-driven Group 3 (G3) MB, remain elusive due to limited druggable mutations, poor blood–brain barrier (BBB) penetration, and rapid resistance. We developed SINBA (Synergy Inference by Data-driven Network-Based Bayesian Analysis), a systems biology framework that predicts synergistic, BBB-permeable drug combinations by identifying hidden drivers that sustain oncogenic programs without detectable genetic or transcriptional alterations. Integrating MB-specific gene networks, transcriptomic data, and drug–gene interactions, SINBA prioritized 32 candidate combinations, of which 19 were experimentally validated as synergistic. The MEK inhibitor mirdametinib and p38 inhibitor regorafenib emerged as the top brain-penetrant pair, suppressing G3 MB progression and extending survival in human xenograft and immunocompetent mouse models, with efficacy enhanced by low-dose radiation. Single-cell analysis revealed selective targeting of the developmental origins of G3 MB, accompanied by immune microenvironment reprogramming. These findings establish hidden-driver inference as a generalizable framework for rational drug combination discovery. Health sciences/Oncology/Cancer/Paediatric cancer Biological sciences/Computational biology and bioinformatics/Statistical methods Biological sciences/Systems biology/Systems analysis Health sciences/Oncology/Cancer/Cancer therapy/Drug development Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTables.xlsx supplementary tables SupplementatyInformation.pdf Supplementary figures Cite Share Download PDF Status: Under Review Version 1 posted 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. 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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-8278592","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":601246369,"identity":"9a396b1c-35e0-49b2-a6b5-800db90fe290","order_by":0,"name":"Jiyang 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