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INSERM / Plan Cancer 2019 - 2022: Evolutionary Mechanisms of Metabolic Adaptation and Scheduling of Therapy in ONcology (250 kE).

Project: This project combines mathematical models integrating heterogeneous phenotypic and genetic data with multiple in vitro models of cancer evolution. Triple Negative Breast Cancers (TNBC) are unsuited to targeted therapy and display high diversity and resistance. We will thus use 3 existing TNBC models, of common origin but subjected to different tumor initiating oncogenic insults, treated over several generations with two drugs targeting antagonist receptors involved in metabolism. By following phenotypic and genetic properties over time, we aim to uncover and quantify how distinct tumor initiation contexts shape evolutionary trajectories and the emergence of resistance. Using mathematical models and simulations, we will investigate how to optimise therapeutic regimens based on the intrinsic evolutionary properties of each model, before validating our predictions in vivo via murine xenografts. Results: The results of this project will help better characterize the influence of the initiating genetic alterations on the ensuing dynamics of development and resistance in TNBC. It will also pave the way to optimise novel therapeutic strategies aiming to leverage cell metabolism to control tumor evolution in the clinic.