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Section: Research Program

Multiscale models in oncology

Project-team positioning

Since 15 years, the development of mathematical models in oncology has become a significant field of research throughout the world. Several groups of researchers in biomathematics have developed complex and multiscale continuous and discrete models to describe the pathological processes as well as the action of anticancer anti-cancer drugs. Many groups in US (e.g. Alexander Anderson's lab, Kristin Swansson's lab) and in Canada (e.g. Thomas Hillen, Gerda de Vries), quickly developed and published interesting modeling frameworks. The setup of European networks such as the Marie Curie research and training networks managed by Nicolas Bellomo and Luigi Preziosi constituted a solid and fertile ground for the development of new oncology models by teams of biomathematicians and in particular Zvia Agur (Israel), Philip Maini (UK), Helen Byrne (UK), Andreas Deutsch (Germany), or Miguel Herrero (Spain).

Results

We have worked on the development of a multiscale system for modeling the complexity of the cancer disease and generate new hypothesis on the use of anti-cancer drugs. This model relies on a multiscale formalism integrating a subcellular level integrating molecular interactions, a cell level (integrating the regulation of the cell cycle at the levels of individual cells) and a macroscopic level for describing the spatio-temporal dynamics of different types of tumor tissues (proliferating, hypoxic and necrotic). The model is thus composed by a set of partial differential equations (PDEs) integrating molecular network up to tissue dynamics using lax from fluid dynamic. This formalism is useful to investigate theoretically different cancer processes such as the angiogenesis and invasion. We have published several examples and case studies of the use of this model in particular, the action of phase-specific chemotherapies (Ribba, You et al. 2009), the use of anti-angiogenic drugs (Billy, Ribba et al. 2009) and their use in combination with chemotherapies (Lignet, Benzekry et al. 2013). This last work also integrates a model of the VEGF molecular pathway for proliferation and migration of endothelial cells in the context of cancer angiogenesis (Lignet, Calvez et al. 2013).

If these types of models present interesting framework to theoretically investigate biological hypothesis, they however present limitation due to their large number of parameters. In consequence, we decided to stop the development of the multiscale platform until exploration of alternative modeling strategies to deal with real data. We focus our interest on the use of mixed-effect modeling techniques as classically used in the field of pharmacokinetic and pharmacodynamics modeling. The general principal of this approach lies in the integration of several levels of variability in the model thus allowing for the simultaneous analysis of data in several individuals. Nowadays, complex algorithms allow for dealing with this problem when the model is composed by few ordinary differential equations (ODEs). However, no similar parameter estimation method is available for models defined as PDEs. In consequence, we decided: 1. To develop more simple models, based on systems of ODEs, assuming simplistic hypothesis of tumor growth and response to treatment but with a real focus on model ability to predict real data. 2. To work alone the development of parameter estimation methods for PDE models in oncology.