Proefschrift

CHAPTER 1. INTRODUCTION Figure 1.5: Schematic of the standard of care maximum tolerated dose treatment (top) and adaptive therapy (bottom). During standard of care, the treatment is given at the maximum tolerated dose and is given continuously. This provides an initial dramatic decrease of tumor burden, likely due to the eradication of the sensitive cells, as seen with all sensitive (blue) cells disappearing. Unfortunately even as treatment continues, the resistant (orange) cells can grow unconstrained. In adaptive therapy, a potentially lower dose is given for a short period of time. While this does eliminate some sensitive cells, it leaves a large population of them in the tumor. When no treatment is given, these sensitive cells regrow suppressing the resistant cells. This cycling is continued to keep the tumor under control. et al., 2008; Shimada and Aihara, 2008; Tao et al., 2010; Jain et al., 2011; Hirata et al., 2018a). ADT is the chemical equivalent of physical castration, attempting to remove the main hormonal driver of prostate cancer. Unfortunately, this treatment invariably fails in the clinic, where patients progress to what is known as metastatic castrate-resistant prostate cancer (mCRPC). Once a patient progresses to mCRPC, there are many options for secondary line therapy, with one of the most common being abiraterone. This thesis develops a mathematical model to understand the eco-evolutionary first principles underlying response to this secondary line therapy, abiraterone. The mathematical model developed here does not attempt to fully describe every underlying biological process of mCRPC, but instead focuses on clinically known cell types and their interaction with the drug abiraterone. In this way, this mathematical model is not intended to exactly recreate clinical data. Instead, the mathematical model is used to identify critical parameters that affect system dynamics, generate experimentally testable hypotheses, and generally provide an increased understanding of the first principles of evolution of resistance to treatment with abiraterone. 12