An integrated network-based mechanistic model for tumor growth dynamics under drug administration

Cancer chemotherapy complexity ranges from the routes that the drug must follow before reaching the tumor site (pharmacokinetics), to the drug effects on tumor depletion (pharmacodynamics). Previous researchers, in their majority, have focused either on the pharmacokinetics (PK) or on the pharmacodynamics (PD) aspects of chemotherapy. Moreover, models that account for the molecular mechanisms of cancer development have limited scope in addressing the protein signals involved in tumor progression. For instance, the recently developed models for the p53 network, for which a number of mutations have been reported, must be integrated for further understanding of the disease. Here, we propose an integrated model that is composed of a compartmental PK/PD representation for drug therapy that incorporates p53 and cell cycle regulation. In particular, the dynamics of p53 and its network components, such as Mdm2, pRb, cyclin-cdk's, are modeled under drug administration. The results show that the proposed model is a realistic representation of the physiological expectations in a multi-scale, integrative approach.