Section: New Results

Model-based Optimization of Cancer Chronotherapies

Participants : Elisabetta De Maria, François Fages, Aurélien Rizk, Sylvain Soliman, Denis Thieffry.

Recent advances in cancer chronotherapy techniques support the evidence that there exist some links between the cell cycle and the circadian clock genes. One purpose for modeling the entrainment in period of the cell cycle by the circadian clock is to better understand how to efficiently target malignant cells depending on the phase of the day and patient characterictics. This is at the heart of our participation in collaboration with the EPI BANG in the EraNet SysBio project C5Sys , follow up of the former EU STREP project TEMPO .

In [4] we show how temporal logic constraints, and the new features of BIOCHAM for parameter search (running on a cluster of 10000 processors at the GENCI) can be used to couple dynamical models in high dimension and more precisely to build a coupled model composed of:

• a four phases model of the mammalian cell cycle by Novak and Tyson,

• a circadian clock model by Leloup and Goldbeter,

• a DNA damage repair model by Ciliberto et al.,

• a model of irinotecan metabolism by Dimitrio and Ballesta,

• a simple model of drug administration control.

This coupled model allows us to minimize the toxicity of irinotecan on healthy cells, using BIOCHAM's parameter search method applied on the drug administration control law.

Our technology is ready to calibrate models on real patient data, evaluate model predictions and optimize patient-tailored chronotherapeutics. The collaboration currently focuses on the obtaining of consistent data in the C5Sys project and on the improvement of the cell cycle model.