Proefschrift

trials of additional androgen blockade therapies, many of which are still the standard of care for today’s patients. Unfortunately, it is explicitly known, and even Huggins commented on that in 1941, that while these types of systemic treatments can provide benefit, they are never curative (Huggins and Hodges, 1972; Prostate Cancer Trialists’ Collaborative Group, 1995). Also in the late 1960’s, by studying prostate tissue extracts taken from biopsy samples, antigens with properties specific to the prostate organ were characterized (De Angelis et al., 2007). In the late 1970’s, this prostate specific antigen (PSA) was successfully purified and characterized, allowing it to be used as a biomarker for prostate cancer (Wang et al., 1979). PSA is now commonly used as both a means for early detection of prostate cancer, as well as a proxy for total tumor volume within a patient, to monitor the response of prostate cancer to treatment. Of the estimated 18 million cancer cases around the world in 2018, 7.5% of them were prostate cancer diagnoses (Bray et al., 2018). It is estimated that there will be over 1.4 million men diagnosed with prostate cancer by the end of 2020 alone. Fortunately, due to the advances in early detection and surgical techniques, the 5-year survival rate for local prostate cancer is 100%. Unfortunately, once prostate cancer spreads away from the primary site to distant organs and becomes what is known as metastatic prostate cancer (mPC), the 5-year survival rate drops drastically to 28.7% (Jemal et al., 2017). In general, across all cancers, metastatic disease remains invariably fatal with an average 5-year survival of only 22%. Since the discovery of androgen blockade therapy and the biomarker PSA in the late 1960’s and 70’s, a plethora of novel therapeutics have been approved by the Food and Drug Administration (FDA) for the treatment of mPC (Table 1.1). Frighteningly, the 5-year overall survival for patients with mPC in 1975-1977 was 31.8%, actually 3.1% better than the most current 2006-2012 data (Jemal et al., 2017). 1.2 The Cause of Treatment Failure Why do all of these therapies, which have been shown in phase III clinical trials to provide some level of therapeutic effect, fail to result in a cure of metastatic prostate cancer? It is now known that cancer cells undergo classic Darwinian evolution that results in the acquisition of resistance mechanisms that render therapies ineffective (Nowell, 1976; Michor et al., 2006; Gatenby and Brown, 2018). This ability to evolve resistance to therapy is arguably the leading problem in cancer therapy today. Since the early 2000’s, the reframing of cancer as a process undergoing natural selection from internal pressures (e.g. resource limitation, acidity, low oxygen) and external pressures (therapies, immune system) has dramatically changed how cancer as a whole is understood. It is now widely accepted that tumors, within and between patients, are remarkably heterogeneous both genotypically and phenotypically (Gerlinger et al., 2012; Venkatesan and Swanton, 2016). This intratumoral heterogeneity has a direct effect on the response of a tumor to any given therapy. When a therapy is initially applied to a heterogeneous tumor, a majority of the cancer cells will be sensitive to the treatment, but there may be a small subset of 5