Optimal control of cytotoxic and antiangiogenic therapies on prostate cancer growth

Abstract

Prostate cancer can be lethal in advanced stages, for which chemotherapy may become the only viable therapeutic option. While there is no clear clinical management strategy fitting all patients, cytotoxic chemotherapy with docetaxel is currently regarded as the gold standard. However, tumors may regain activity after treatment conclusion and become resistant to docetaxel. This situation calls for new delivery strategies and drug compounds enabling an improved therapeutic outcome. Combination of docetaxel with antiangiogenic therapy has been considered a promising strategy. Bevacizumab is the most common antiangiogenic drug, but clinical studies have not revealed a clear benefit from its combination with docetaxel. Here, we capitalize on our prior work on mathematical modeling of prostate cancer growth subjected to combined cytotoxic and antiangiogenic therapies, and propose an optimal control framework to robustly compute the drug-independent cytotoxic and antiangiogenic effects enabling an optimal therapeutic control of tumor dynamics. We describe the formulation of the optimal control problem, for which we prove the existence of at least a solution and determine the necessary first-order optimality conditions. We then present numerical algorithms based on isogeometric analysis to run a preliminary simulation study over a single cycle of combined therapy. Our results suggest that only cytotoxic chemotherapy is required to optimize therapeutic performance and we show that our framework can produce superior solutions to combined therapy with docetaxel and bevacizumab. We also illustrate how the optimal drug-naïve cytotoxic effects computed in these simulations may be successfully leveraged to guide drug production and delivery strategies by running a nonlinear least-square fit of protocols involving docetaxel and a new design drug. In the future, we believe that our optimal control framework may contribute to accelerate experimental research on chemotherapeutic drugs for advanced prostate cancer and ultimately provide a means to design and monitor its optimal delivery to patients.