{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:36:44Z","timestamp":1785418604775,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSW Health"},{"name":"Sydney West Radiation Oncology Network"},{"name":"Cancer Institute NSW Career Development Fellowship"},{"DOI":"10.13039\/501100006641","name":"Cure Brain Cancer Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006641","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02db9yt31","id-type":"ROR","asserted-by":"publisher"}]},{"name":"DIPG\/DMG Collaborative"},{"name":"Cure Starts Now"},{"DOI":"10.13039\/501100022712","name":"Mark Hughes Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022712","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008221","name":"Cure Starts Now Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008221","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04edq9h05","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Cure Starts Now Australia"},{"DOI":"10.13039\/100019369","name":"Brooke Healey Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019369","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Melina Michelle Edenfield Foundation"},{"name":"Cure Starts Now Canada"},{"DOI":"10.13039\/501100016057","name":"Robert Connor Dawes Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100016057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010080","name":"Reflections of Grace Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010080","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00b0e2156","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ayla Foundation"},{"name":"Yuvaan Tiwari Foundation"},{"name":"Aubreigh\u2019s Army Foundation 328"},{"name":"Avery\u2019s Little Army"},{"name":"Whitley\u2019s Wishes"},{"DOI":"10.13039\/100003156","name":"Musella Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100003156","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Anna\u2019s Bake Sale Foundation"},{"name":"Love4Lucas Foundation"},{"name":"Aidan\u2019s Avengers"},{"name":"Run DIPG"},{"name":"Abbie\u2019s Army"},{"name":"Abby\u2019s Corner Foundation"},{"DOI":"10.13039\/501100019893","name":"Isabella and Marcus Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100019893","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lauren\u2019s Fight for Cure, Love, Chloe Foundation"},{"name":"Gold Hope Project"},{"name":"Nadacni fond Nina"},{"name":"Snapgrant.com"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain tumor. Radiotherapy remains the standard of care, but tumors recur due to radioresistance. Tumor hypoxia contributes to radioresistance, and evidence of oxidative metabolism and hypoxia-associated transcriptomic programs suggests that hypoxia may be relevant in DIPG. We therefore investigated the FDA-approved mitochondrial inhibitor atovaquone as a strategy to target oxidative metabolism and enhance radiation response in DIPG. Methods: Patient-derived DIPG cell lines were used to evaluate atovaquone by extracellular flux analysis, hypoxia and reactive oxygen species assays, clonogenic survival assays, metabolomics, and RNA sequencing. To improve brain exposure, an amorphous solid dispersion (ASD) atovaquone formulation was evaluated and tested in an orthotopic DIPG model. Results: In patient-derived DIPG cultures, atovaquone suppressed mitochondrial respiration, reduced hypoxia-associated readouts, decreased HIF-1\u03b1 expression in 3D models, and enhanced radiation response. At higher concentrations, atovaquone also increased oxidative stress and enhanced the radiosensitivity of DIPG monolayers. Transcriptomics analysis revealed disruption of cell-cycle and mitotic pathways, supporting additional treatment-associated effects beyond hypoxia reduction alone. Commercial and ASD formulations showed comparable in vitro activity. In vivo, ASD atovaquone combined with radiation prolonged survival in an orthotopic DIPG model. Conclusions: Targeting mitochondrial metabolism enhances radiosensitivity in DIPG and supports mitochondrial metabolism as a potential therapeutic weakness in this disease. Its effects are associated with reduced hypoxia-related signaling and broader metabolic and transcriptional changes.<\/jats:p>","DOI":"10.3390\/cancers18101553","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"1553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Atovaquone Targets Mitochondrial Metabolism and Enhances Radiosensitivity of Diffuse Intrinsic Pontine Glioma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7070-9590","authenticated-orcid":false,"given":"Faiqa","family":"Mudassar","sequence":"first","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-7166","authenticated-orcid":false,"given":"Kristina M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1028-134X","authenticated-orcid":false,"given":"Zachary N.","family":"Warnken","sequence":"additional","affiliation":[{"name":"Via Therapeutics LLC, Austin, TX 78712-0126, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Bal","sequence":"additional","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey","family":"Lai","sequence":"additional","affiliation":[{"name":"Westmead Research Hub Core Facilities, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Gloss","sequence":"additional","affiliation":[{"name":"Westmead Research Hub Core Facilities, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8233-1553","authenticated-orcid":false,"given":"Holly P.","family":"McEwen","sequence":"additional","affiliation":[{"name":"Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3651-7672","authenticated-orcid":false,"given":"Ryan J.","family":"Duchatel","sequence":"additional","affiliation":[{"name":"Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine M.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Children\u2019s Cancer Research Unit, The Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-8585","authenticated-orcid":false,"given":"Harriet","family":"Gee","sequence":"additional","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Western Sydney Radiation Oncology Network, Sydney, NSW 2145, Australia"},{"name":"Children\u2019s Medical Research Institute, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2435-2150","authenticated-orcid":false,"given":"Han","family":"Shen","sequence":"additional","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Hau","sequence":"additional","affiliation":[{"name":"Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Western Sydney Radiation Oncology Network, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"216876","DOI":"10.1016\/j.canlet.2024.216876","article-title":"Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies","volume":"590","author":"Weisbrod","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1177\/0883073815601495","article-title":"Diffuse Intrinsic Pontine Glioma: Time for Cautious Optimism","volume":"31","author":"Hennika","year":"2016","journal-title":"J. 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