Nonlinear Adaptive Optimal Controller Design for Anti-Angiogenic Tumor Treatment

Angiogenesis is an important process in tumor growth as it represents the regime when the tumor recruits blood vessels from the surrounding tissue to support further tumor growth. Anti-angiogenic treatments aim to shrink the tumor by interrupting the vascularization of the tumor; however, the anti-angiogenic agents are costly and the tumor response to these agents is nonlinear. Simple dosing schemes, e.g., a constant dose, may yield higher cost or lower efficacy than an approach that considers the tumor system dynamics. Hence, in this study, the administration of anti-angiogenic treatment is considered as a nonlinear control problem. The main aim of the controller design is to optimize the anti-angiogenic tumor therapy, specifically, to minimize the tumor volume and drug dose. Toward this aim, two nonlinear optimal controllers are presented. The first controller ensures exponential tracking of a desired, optimal tumor volume profile under the assumption that all parameters in the system model are known. The second controller, on the other hand, assumes all the parameters are unknown and provides asymptotic tracking. Both controllers take pharmacokinetics and pharmacodynamics into account, as well as the carrying capacity of the vascular network. Lyapunov based arguments are used to design the controllers, using stability arguments, and numerical simulation results are presented to demonstrate the effectiveness of the proposed method.