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Exploiting Metabolic Vulnerability in Glioblastoma Using a Brain-Penetrant Drug with a Safe Profile

dc.rights.licenseopenen_US
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
dc.contributor.authorBURBAN, Audrey
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorTESSIER, Cloe
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
dc.contributor.authorPINGLAUT, Mathis
hal.structure.identifierBordeaux population health [BPH]
hal.structure.identifierCentre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
dc.contributor.authorGUYON, Joris
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
dc.contributor.authorGALVIS, Johanna
hal.structure.identifierCentre de Bioinformatique de Bordeaux [CBIB]
dc.contributor.authorDARTIGUES, Benjamin
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorTOUJAS, Maxime
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
hal.structure.identifierCentre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
dc.contributor.authorLARROQUETTE, Mathieu
hal.structure.identifierUniversity of Calgary
dc.contributor.authorLUCHMAN, Artee
hal.structure.identifierUniversity of Calgary
dc.contributor.authorWEISS, Samuel
hal.structure.identifierLuxembourg Institute of Health [LIH]
dc.contributor.authorNICOT, Nathalie
hal.structure.identifierLuxembourg Institute of Health [LIH]
hal.structure.identifierGerman Cancer Consortium [Heidelberg] [DKTK]
hal.structure.identifierNational Center for Tumor Diseases [Dresden] [NCT]
dc.contributor.authorKLINK, Barbara
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
hal.structure.identifierCentre de Bioinformatique de Bordeaux [CBIB]
dc.contributor.authorNIKOLSKI, Macha
IDREF: 134506049
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorBRISSON, Lucie
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorMATHIVET, Thomas
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorBIKFALVI, Andreas
hal.structure.identifierInstitut de biochimie et génétique cellulaires [IBGC]
dc.contributor.authorDAUBON, Thomas
hal.structure.identifierBoRdeaux Institute in onCology [Inserm U1312 - BRIC]
dc.contributor.authorSHARANEK, Ahmad
dc.date.accessioned2025-06-13T09:31:27Z
dc.date.available2025-06-13T09:31:27Z
dc.date.created2024-01-16
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/206904
dc.description.abstractEnGlioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employed in vivo pharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies in mice revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.
dc.language.isoENen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/
dc.title.enExploiting Metabolic Vulnerability in Glioblastoma Using a Brain-Penetrant Drug with a Safe Profile
dc.typeDocument de travail - Pré-publicationen_US
dc.identifier.doi10.1101/2024.01.15.574967en_US
dc.subject.halSciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biologie moléculaireen_US
bordeaux.hal.laboratoriesBRIC (Bordeaux of Institute of Oncology) - U1312en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.import.sourcehal
hal.identifierhal-04833189
hal.version1
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
bordeaux.subtypePrepublication/Preprinten_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.au=BURBAN,%20Audrey&TESSIER,%20Cloe&PINGLAUT,%20Mathis&GUYON,%20Joris&GALVIS,%20Johanna&rft.genre=preprint


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