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Model-driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis

hal.structure.identifierSimulation & Modelling : Adaptive Response for Therapeutics in Cancer [SMARTc unit]
hal.structure.identifierUniversity of Cambridge [UK] [CAM]
dc.contributor.authorMOLLARD, Severine
hal.structure.identifierSimulation & Modelling : Adaptive Response for Therapeutics in Cancer [SMARTc unit]
dc.contributor.authorCICCOLINI, Joseph
hal.structure.identifierSimulation & Modelling : Adaptive Response for Therapeutics in Cancer [SMARTc unit]
dc.contributor.authorIMBS, Diane-Charlotte
hal.structure.identifierSimulation & Modelling : Adaptive Response for Therapeutics in Cancer [SMARTc unit]
dc.contributor.authorEL CHEIKH, Raouf
hal.structure.identifierSimulation & Modelling : Adaptive Response for Therapeutics in Cancer [SMARTc unit]
dc.contributor.authorBARBOLOSI, Dominique
hal.structure.identifierInstitut de Mathématiques de Bordeaux [IMB]
hal.structure.identifierModélisation Mathématique pour l'Oncologie [MONC]
dc.contributor.authorBENZEKRY, Sébastien
dc.date.accessioned2024-04-04T03:10:54Z
dc.date.available2024-04-04T03:10:54Z
dc.date.issued2017
dc.identifier.issn1949-2553
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/193724
dc.description.abstractEnBevacizumab is the first-in-class antiangiogenic drug and is almost always administrated in combination with cytotoxics. Reports have shown that bevacizumab could induce a transient phase of vascular normalization, thus ensuring a better drug delivery when cytotoxics administration is adjuvant. However, determining the best sequence remains challenging. We have developed a mathematical model describing the impact of antiangiogenics on tumor vasculature. A 3.4 days gap between bevacizumab and paclitaxel was first proposed by our model. To test its relevance, 84 mice were orthotopically xenografted with human MDA-231 Luc+ refractory breast cancer cells. Two sets of experiments were performed, based upon different bevacizumab dosing (10 or 20 mg/kg) and inter-cycle intervals (7 or 10 days), comprising several combinations with paclitaxel. Results showed that scheduling bevacizumab 3 days before paclitaxel improved antitumor efficacy (48% reduction in tumor size compared with concomitant dosing, p < 0.05) and reduced metastatic spreading. Additionally, bevacizumab alone could lead to more aggressive metastatic disease with shorter survival in animals. Our model was able to fit the experimental data and provided insights on the underlying dynamics of the vasculature's ability to deliver the cytotoxic agent. Final simulations suggested a new, data-informed optimal gap of 2.2 days. Our experimental data suggest that current concomitant dosing between bevacizumab and paclitaxel could be a sub-optimal strategy at bedside. In addition, this proof of concept study suggests that mathematical modeling could help to identify the optimal interval among a variety of possible alternate treatment modalities, thus reining the way experimental or clinical studies are conducted.
dc.description.sponsorshipINITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - ANR-11-IDEX-0001
dc.language.isoen
dc.publisherImpact journals
dc.subject.enantiangiogenics
dc.subject.enscheduling
dc.subject.encombination
dc.subject.enmathematical modeling
dc.subject.entumor vasculature normalization
dc.title.enModel-driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis
dc.typeArticle de revue
dc.identifier.doi10.18632/oncotarget.15484
dc.subject.halSciences du Vivant [q-bio]/Cancer
bordeaux.journalOncotarget
bordeaux.hal.laboratoriesInstitut de Mathématiques de Bordeaux (IMB) - UMR 5251*
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionBordeaux INP
bordeaux.institutionCNRS
bordeaux.peerReviewedoui
hal.identifierhal-01474679
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-01474679v1
bordeaux.COinSctx_ver=Z39.88-2004&amp;rft_val_fmt=info:ofi/fmt:kev:mtx:journal&amp;rft.jtitle=Oncotarget&amp;rft.date=2017&amp;rft.eissn=1949-2553&amp;rft.issn=1949-2553&amp;rft.au=MOLLARD,%20Severine&amp;CICCOLINI,%20Joseph&amp;IMBS,%20Diane-Charlotte&amp;EL%20CHEIKH,%20Raouf&amp;BARBOLOSI,%20Dominique&amp;rft.genre=article


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