Computational-Model-Based Biopharmaceutics for p53 Pathway Using Modern Control Techniques for Cancer Treatment

Abstract

The p53 pathway has been the focus of many researchers in the last few decades owing to its pivotal role as a frontline cancer suppressant protein. It plays a vital role in maintaining cell cycle checkpoints and cell apoptosis in response to a broken DNA strand. This is why it is found in the mutated form in more than 50% of malignant tumors. To overcome this, various drugs have been proposed to revive the p53 pathway in cancer patients. Small-molecule-based drugs, such as Nutlin 3a, which are capable of performing this stimulation, are at the fore of advanced clinical trials. However, the calculation of their dosage is a challenge. In this work, a method to determine the dosage of Nutlin 3a is investigated. A control-systems-based model is developed to study the response of the wild-type p53 protein to this drug. The proposed strategy regulates the p53 protein along with negative and positive feedback loops mediated by the MDM2 and MDM2 mRNA, respectively, along with the reversible repression of MDM2 caused by Nutlin 3a. For a broader perspective, the reported PBK dynamics of Nutlin 3a are also incorporated. It has been reported that p53 responds to stresses in two ways in terms of concentration to this drug: either it is a sustained (constant) or an oscillatory response. The claimed dosage strategy turned out to be appropriate for sustained p53 response. However, for the induction of oscillations, inhibition of MDM2 is not enough; rather, anti-repression of the p53–MDM2 complex is also needed, which opens new horizons for a new drug design paradigm.

Keywords

• p53 pathway
• cancer treatment
• MDM2 inhibition