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 1 , Diane-Charlotte Imbs 1 , Raouf El Cheikh 1 , Dominique Barbolosi 1 , Sebastien Benzekry 3 1 SMARTc Unit, Inserm S_911 CRO2, Aix Marseille University, Marseille, France 2 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 3 MONC Team, INRIA, Bordeaux, France Correspondence to: Sebastien Benzekry, email: sebastien.benzekry@inria.fr Keywords: tumor vasculature normalization, antiangiogenics, scheduling, combination, mathematical modeling Received: November 30, 2016      Accepted: February 07, 2017      Published: February 18, 2017 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 modelling could help to identify the optimal interval among a variety of possible alternate treatment modalities, thus refining the way experimental or clinical studies are conducted.