Proefschrift

CHAPTER 8. SUMMARY stable tumor heterogeneity of sensitive and resistant cells to abiraterone in order to prolong treatment efficacy and progression free survival. Surprisingly, optimal control analysis shows that a dose titration protocol, a very common dosing strategy in other medical disciplines, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may, counterintuitively, be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, again suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations. In Chapter 7, the results from this thesis are placed within the context of current clinical and mathematical oncology and future directions are discussed in detail. In particular, a framework for using model predictive control methods are described for implementing evolutionary therapy as a real-time clinical treatment protocol to govern proliferation of resistant cancer cells. Furthermore, a number of clinically available options for measuring the sensitive vs. resistant tumor composition are discussed in detail including blood serum markers, imaging, and liquid biopsy. Lastly, current clinical trials that were inspired by the results in this thesis are presented. In conclusion, the ultimate goal of treating cancer is for the patient to remain alive. This is not synonymous with eradicating all tumor cells in the body. In this way, clinical success must be redefined as cumulative years of survival with acceptable quality of life regardless of tumor burden. This will require, first and foremost, the discontinuation of the maximum tolerated dose paradigm for available non curative therapies. Instead, each available therapy should be administered using a resistance management plan that judiciously applies therapy guided by the dynamics of each patient’s specific disease. Based on the results from this thesis, it is not unreasonable to assume that the time a drug is effective using MTD can be at least doubled in the clinic using evolutionary enlightened dosing strategies. If overall survival can indeed be doubled for the therapies available, men with metastatic prostate cancer could potentially manage their disease for well over 10 years: an extraordinary clinical achievement. Associated Publications of Thesis Chapters Chapter 2 is adapted from Cunningham, J. (2019) A call for integrated metastatic management. Nature Ecology & Evolution , 3(7), pp.996-998. Chapter 4 is adapted from Zhang, J., Cunningham, J., Brown, J. and Gatenby, R. (2017) Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nature Communications , 8(1), pp.1-9. Chapter 5 is adapted from Cunningham, J., Brown, J., Gatenby, R. and Stanˇkova´, K. (2018) Optimal control to develop therapeutic strategies for metastatic castrate-resistant prostate cancer. Journal of Theoretical Biology , 459, pp.67-78. Chapter 6 is adapted from Cunningham, J., Thuijsman, F., Peeters, R., Viossat, Y., Brown, J., Gatenby, R. and Stanˇkova´, K. (2020) Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer. PloS One , 15(12), pp.e0243386. 120