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

Severine Mollard 1, 2 Joseph Ciccolini 2 Diane-Charlotte Imbs 2 Raouf El Cheikh 2 Dominique Barbolosi 2 Sébastien Benzekry 3, 4
2 SMARTc
CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
4 MONC - Modélisation Mathématique pour l'Oncologie
IMB - Institut de Mathématiques de Bordeaux, Inria Bordeaux - Sud-Ouest, Institut Bergonié - CRLCC Bordeaux
Abstract : Bevacizumab 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.
Type de document :
Article dans une revue
Oncotarget, Impact journals, 2017, 〈10.18632/oncotarget.15484〉
Liste complète des métadonnées

Littérature citée [24 références]  Voir  Masquer  Télécharger

https://hal.inria.fr/hal-01474679
Contributeur : Sebastien Benzekry <>
Soumis le : jeudi 23 février 2017 - 09:12:05
Dernière modification le : lundi 29 janvier 2018 - 17:30:06
Document(s) archivé(s) le : mercredi 24 mai 2017 - 12:32:25

Fichier

Mollard_17_Oncotarget_Model dr...
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

Severine Mollard, Joseph Ciccolini, Diane-Charlotte Imbs, Raouf El Cheikh, Dominique Barbolosi, et al.. 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. Oncotarget, Impact journals, 2017, 〈10.18632/oncotarget.15484〉. 〈hal-01474679〉

Partager

Métriques

Consultations de la notice

439

Téléchargements de fichiers

169