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Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.<\/jats:p>","DOI":"10.3390\/cancers16091754","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T04:01:52Z","timestamp":1714449712000},"page":"1754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Antiretroviral Drug Repositioning for Glioblastoma"],"prefix":"10.3390","volume":"16","author":[{"given":"Sarah R.","family":"Rivas","sequence":"first","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA"},{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mynor J.","family":"Mendez Valdez","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-3579","authenticated-orcid":false,"given":"Jay S.","family":"Chandar","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelisah F.","family":"Desgraves","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor M.","family":"Lu","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Ampie","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Singh","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Seetharam","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian K.","family":"Ramsoomair","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Hudson","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya M.","family":"Ingle","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaidya","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1117-2006","authenticated-orcid":false,"given":"Tara T.","family":"Doucet-O\u2019Hare","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"DeMarino","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3890-0165","authenticated-orcid":false,"given":"John D.","family":"Heiss","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avindra","family":"Nath","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Section of Virology and Immunotherapy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, 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