Control Oriented Dosage Design for p53 Revival


In the last few decades, cancer has become one of the leading causes of death in the human race. A signi cant loss of the p53 protein, an anti-tumor agent, is observed in early cancerous cells (in around 50% of cancer cases). The p53 protein is being studied widely due to its pivotal role as a potential drug target. The induction of small molecules based drug Nutlin is by far the most prominent technique to revive and maintain wild-type p53 to the desired levels. The current research work proposes a systems theory-based novel drug dosage design for the p53 pathway. The pathway is taken as a dynamic system represented by ordinary differential equations (ODEs). Using control engineering practices, the system analysis and subsequent controller design are performed for the re-activation of wild-type p53.

For this purpose, two control strategies are adopted. In the rst strategy, the attractor point analysis is carried out to select a suitable domain of attraction. A two-loop negative feedback control strategy is devised to drag the system trajectories to the attractor point. An integrated framework is constituted to incorporate the pharmacokinetic effects of Nutlin in the cancerous cells. In the second control strategy, a sliding mode control (SMC) based robust non-linear technique is presented for the drug dosage design of a control-oriented p53 model. The control input generated by the conventional SMC is discontinuous, however, depending on the physical nature of the system, the drug infusion needs to be continuous. Therefore, to obtain a smooth control signal, a dynamic SMC (DSMC) is designed. To make the model-based control design possible, the unknown states of the system are estimated using equivalent control based, reduced-order sliding mode observer (SMO). The robustness of the proposed technique is assessed by introducing input disturbance measurement noise, and parametric uncertainty in the system. The effectiveness of the proposed control scheme is witnessed by performing in silico trials, revealing that the sustained level of p53 can be achieved by controlled drug administration. Moreover, a comparative quantitative analysis shows that both controllers yield similar performance. However, DSMC consumes less control energy.

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