Abstract B11: Adaptive therapy modifies tumor vascularity

Introduction: Disseminated cancers are typically treated with the highest possible dose of drug (i.e. maximum tolerated dose) to achieve the goal of killing as many tumor cells as possible. However, these therapies eventually fail due to emergence of resistant clones. We have predicted, using mathematical models of Darwinian dynamics, that treatment regimens that adapt the dosing to the tumor spatial variability and tumor microenvironment, can retard the emergence of chemoresistance. Here we present an evolutionary-guided treatment strategy (Adaptive Therapy, AT) designed to maintain stable chemosensitive populations while limiting the proliferation of chemoresistant clones by exploiting the fitness cost of the resistant phenotype. We also evaluated how this novel treatment strategy modifies tumor vascularity. Methods: Four cohorts (composed by 12, 11, 13, and 10 mice, respectively) of nude mice were injected with 10x10 6 MDA-MB-231 (triple-negative breast cancer) cells in the mammary fat pad. Control animals didn9t receive any treatment. Mice under standard therapy received 20mg/kg of Tamoxifen twice per week for a total of 5 times. We defined two different Tamoxifen AT algorithms (Table 1), under which AT mice were treated. When the tumors achieve the volume of, approximately 300 mm 3 , MRI T 2 and Diffusion Weighted acquisitions were performed on a horizontal Agilent ASR 310 7T scanner, with 205/120/HDS gradients and 310 mm bore to determine volume and cellularity, respectively. Thereafter, dynamic contrast enhanced (DCE-) MRI was preformed following bolus of 0.1mmol/kg Magnevist to assess distribution of blood flow. Images were processed with different in-house developed MATLAB scripts to obtain reliable information from these images. At the end of the monitoring time, tumors were collected and processed for HE Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B11.