In clinical practice, antiangiogenic bevacizumab is usually administrated concomitantly to the chemotherapy. Still, pharmacodynamics effect of antiangiogenics lead to a transient state of normalization of the vessels, thus increasing tumor blood perfusion. This could be used as a time-window for administrating cytotoxics, so as to maximize the amount of drugs reaching the tumor eventually. Our group has developed original mathematical models describing the impact of bevacizumab on tumor vasculature. Simulations have demonstrated in silico that a 6-days lag between the administration of bevacizumab and starting the chemotherapy is recommended to achieve antitumoral efficacy. To test this hypohesis, we have used a breast cancer model to compare the efficacy, tolerance and impact on metastatic spreading of a variety of combinations between bevacizumab and paclitaxel. Fifty NSG mice were grafted with resistant MDA-MB-231-LUC+ human breast cancer cells. Animals were next randomized into 6 groups (control, bevacizumab (B), paclitaxel (T) bevacizumab + pacitaxel (B+T), bevacizumab then paclitaxel (B/T), and paclitaxel then bevacizumab (T/B)). Tumor growth and metastatic spreading were monitored by bioluminescence 3D. Main endpoints were overall survival, tolerance, tumor growth and metastatic spreading. At 60 days, survival was 100% (B/T), 85% (B+T), 75% (T), 65% (T/B), 35% (B) and 0% (control). Additionally, sequences proved to have a strong impact on both timing and localization of the metastatic spreading. Bevacizumab alone led to a metastatic acceleration, since lesions appeared earlier, even as compared with untreated animals. Conversely, the (B/T) sequence reduced significantly the risk of lymph-node metastatis, as compared with any other combinations (i.e., 10% (B/T) vs. 25 and 40% for (B+T) and (T/B), respectively), whereas 100% of untreated animals showed lymph node metastatis. Large inter-individual variability within the groups led to non-significant differences in tumor size at study conclusion, despite the fact that marked reduction in tumor volume was achieved in the (B/T) group. Finally, the (B/T) combination proved to be the best tolerated one. Our present data strongly suggest that refining the sequence in the administration of drugs is critical to improve both tolerance and efficacy. Here, the (B/T) association proved to be more efficacious than any other modalities, especially to reduce and to delay metastatis. Conversely, bevacizumab alone proved to accelerate metastatic spreading. Although preliminary, this POC study demonstrates the relevance of our mathematical model, since predictions of the model have been fully confirmed at the bench. This model could be further used to test in silico various combinations with other anti-angiogenic drugs, so as to identify the best modality of combination prior to use those drugs in vivo.

Citation Format: Severine Mollard, Sebastien Benzekry, Sarah Giacometti, Christian Faivre, Florence Hubert, Joseph Ciccolini, Dominique Barbolosi. Model-based optimization of combined antiangiogenic + cytotoxics modalities: application to the bevacizumab-paclitaxel association in breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3677. doi:10.1158/1538-7445.AM2014-3677