Optimizing Dosage-Specific Treatments in a Multi-Scale Model of a Tumor Growth

Abstract

The emergence of cell resistance in cancer treatment is a complex phenomenon that emerges from the interplay of processes that occur at different scales. For instance, molecular mechanisms and population-level dynamics such as competition and cell-cell variability have been described as playing a key role in the emergence and evolution of cell resistances. Multi-scale models are a useful tool for studying biology at very different times and spatial scales, as they can integrate different processes occurring at the molecular, cellular, and intercellular levels. In the present work, we use an extended hybrid multi-scale model of 3T3 fibroblast spheroid to perform a deep exploration of the parameter space of effective treatment strategies based on TNF pulses. To explore the parameter space of effective treatments in different scenarios and conditions, we have developed an HPC-optimized model exploration workflow based on EMEWS. We first studied the effect of the cells' spatial distribution in the values of the treatment parameters by optimizing the supply strategies in 2D monolayers and 3D spheroids of different sizes. We later study the robustness of the effective treatments when heterogeneous populations of cells are considered. We found that our model exploration workflow can find effective treatments in all the studied conditions. Our results show that cells' spatial geometry and population variability should be considered when optimizing treatment strategies in order to find robust parameter sets.

Keywords: TNF; agent-based model; cell resistance; model exploration; multi-scale modeling; multi-scale modeling and simulation; optimization via simulation; treatment optimization.