Abstract LB-284: Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer

Abstract

Abstract Background: HER2-positive (HER2+) breast cancer (BC) is more quickly-growing and aggressive than other types of BC. Trastuzumab (TZM) is a humanized monoclonal antibody directed against HER2 receptor. It is clinically used for BC in combination with paclitaxel (PAC) in a 24 h sequence treatment during the first week of therapy followed by a simultaneous administration during the subsequent weeks. To our knowledge there is no scientific rationale for such therapeutic regimes. We propose to develop and optimize a sequential combination of PAC+TZM to optimize their anti-tumoral activity, and hence, HER2+ BC patients’ outcome. Method: Six therapeutic regimens were investigated in vivo on Balbc nude mice xenografted with BT474 cells, a human breast cancer cell line that overexpresses HER2 receptor, including 1) a tumor priming regimen (TPR) with PAC administered 24 h prior to TZM, 2) reverse-TPR with TZM administration first then PAC 24 h later, 3) simultaneous administration of both drugs, 4) PAC alone, 5) TZM alone, 6) vehicle as a control. The doses were 10 and 3 mg/kg for PAC and TZM. The anti-tumoral response in all treatment arms was monitored over time through the measurement of the reduction in tumor volumes as well as animals survival. Results: In vivo studies showed a greater tumor volume shrinkage response in the animals from the TPR treatment arm compared to the other therapeutic schemes with: 1) an enhanced in vivo antitumor response, and 2) a longer animal survival. These results support our in vitro findings of drug synergy and apoptosis. Conclusion: TPR anti-tumor results are promising. The proposed research will develop and employ a systems pharmacology model based on our results to hypothesize optimal regimens for the association (PAC+TZM) breast cancer killing, which will be tested in vivo. Citation Format: Sihem Ait-Oudhia. Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-284.