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The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype\u2013specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine\/rifamycin and cannabidiol\/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I\/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.<\/jats:p>","DOI":"10.1093\/bib\/bbae199","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T10:30:48Z","timestamp":1714732248000},"source":"Crossref","is-referenced-by-count":3,"title":["Metabolic models predict fotemustine and the combination of eflornithine\/rifamycin and adapalene\/cannabidiol for the treatment of gliomas"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3710-5909","authenticated-orcid":false,"given":"Ali","family":"Kishk","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Medicine, University of Luxembourg , L-4367 Belvaux , Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-8093","authenticated-orcid":false,"given":"Maria","family":"Pires Pacheco","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Medicine, University of Luxembourg , L-4367 Belvaux , Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tony","family":"Heurtaux","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Medicine, University of Luxembourg , L-4367 Belvaux , Luxembourg"},{"name":"Luxembourg Centre of Neuropathology , L-3555 Dudelange , Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Sauter","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Medicine, University of Luxembourg , L-4367 Belvaux , Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"2024050310302993200_ref1","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/noac202","article-title":"CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015\u20132019","volume":"24","author":"Ostrom","year":"2022","journal-title":"Neuro-Oncology"},{"issue":"8","key":"2024050310302993200_ref2","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: a summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"issue":"7","key":"2024050310302993200_ref3","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics13071053","article-title":"Glioblastoma multiforme\u2014a look at the past and a glance at the 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