Proefschrift

10000 times. This chapter is a first of its kind publication in which a mathematical model is used to inform a clinical trial. This opened the doors for many other clinical trials based on evolutionary principles including a second trial in prostate cancer (NCT03511196), a trial in thyroid cancer (NCT03630120), a trial in pediatric rhabdomyosarcoma (NCT04388839), and a trial in melanoma (NCT03543969). Furthermore, this work provided proof of concept that led to the development of the Evolutionary Tumor Board (NCT04343365), which aims to further integrate evolutionary ideas into therapeutic strategies for patients without curative options. The Evolutionary Tumor Board brings together evolutionary biologists, mathematicians, research scientists, statisticians, data scientists, radiologists, pathologists, oncologists (surgical, radiation, medical, and pediatric), and clinical trial coordinators into a highly collaborative environment where evolutionary therapy can be designed and implemented for each patient individually. Societal Impact First and foremost, this thesis provides a clear, direct improvement in the clinical treatment of metastatic prostate cancer. The trial presented in Chapter 4 shows that judiciously applying abiraterone in a way that explicitly attempts to delay or prevent the evolution of resistance increased the median time to progression of 16 men to 30.4 months, compared to only 14.3 months for a cohort of 16 men receiving standard dosing of abiraterone. Furthermore, this doubling of time to progression was achieved using, on average, 59% less cumulative abiraterone. It’s worth repeating that the ultimate goal of treating cancer is for the patient to remain alive. This thesis presents long-term management of non-curable metastatic disease as a valid treatment option. Like the long term management of HIV and diabetes, this thesis shows proof of concept of a ‘functional cure’ of metastatic disease. Evolutionary guided therapy can provide high quality of life for long periods of time while also limiting both the physical toxicity and financial burden to the patient. Clinical oncologists and pharmaceutical companies are the primary target audiences for this thesis. Clinicians will be instrumental in a continued push to open clinical trials integrating evolution-based principles into patient care. Furthermore, clinicians and patients can use the results of this thesis to begin to redefine clinical success of treatment of metastatic disease to mean cumulative years of survival with acceptable quality of life. Pharmaceutical companies could benefit from the drastically lengthened time that currently available drugs remain effective by supporting the use of the alternative dosing strategies presented here. Furthermore, when pharmaceutical companies perform phase II and III clinical trials for newly developed drugs, evolutionary guided dosing protocols should be considered for standard of care. Of course, a lot of work remains to be done to improve our understanding of cancer as an evolutionary process and how to best use therapies to control it. It is possible that within our lifetime, people will be living with, rather than dying from, cancer. The continued study and development of Integrated Metastatic Management, like that presented in this thesis for prostate cancer, can provide a way forward in truly revolutionizing clinical cancer care. 123