Proefschrift

CHAPTER 8. SUMMARY While overall survival of early stage prostate cancer is increasing due to early detection and improving therapy for local and regionally confined disease, the 5-year overall survival for metastatic prostate cancer patients has actually dropped by 3.1% (from 31.8% to 28.7%) since 1977. This is despite the increasing number of agents available for treating metastatic prostate cancer. Why, then, do all of these therapies, which have been shown to provide some level of therapeutic effect, fail to result in a higher survival rate of metastatic prostate cancer? It is now known that metastatic cancer populations possess the ability to evolve resistance to all currently available therapies, rendering them ineffective even after an initial strong response. When a therapy is initially applied to a tumor, a majority of the cancer cells will be sensitive to the treatment, but there may be a small subset of cells that are already resistant or can quickly evolve resistance to the treatment due to their evolutionary history. In this way, when treatment is applied, a strong initial response is generally observed, as the treatment is effective against the abundant sensitive cells. Just as antibiotics kill 99.99% of bacteria, this initial therapy may kill 99.99% of the cancer cells, resulting in a clinical remission of disease. Unfortunately, as therapy is continued, the resistant cells initially present or cells that evolved a novel resistance mechanism in direct response to therapy can continue to proliferate causing disease relapse. This ability of cancer cells to evolve resistance to therapy is arguably the leading problem in cancer therapy today. Even with this new understanding of cancer as a Darwinian disease, evolutionary principles are generally not considered in the design of clinical treatment. Instead, the conventional treatment strategy used universally in the clinic in an attempt to eradicate every cancer cell is known as maximum tolerated dose (MTD). Decades of clinical observation have clearly demonstrated that a cure using MTD is rarely possible. For example, this thesis focuses on the use of the drug abiraterone in patients with metastatic castrate-resistant prostate cancer (mCRPC). When given continuously at MTD, abiraterone provides a strong initial response, but invariably, the cancer progresses within a median time of 16 months. This failure is rooted in the very design of MTD which precipitates a “resistance crisis.” MTD strongly selects for already present resistant cell types by eliminating the sensitive cell population and by enforcing strong selection pressures for evolution of novel resistance mechanisms during treatment. In Chapter 2 , this “resistance crisis” of metastatic disease is compared to the “resistance crisis” that occurred during the initial attempts of the agriculture industry to eradicate major pests. The development of a large variety of synthetic pesticides and their subsequent widespread high dose usage began in the 1940s. While the impact on the pest population was initially dramatically successful, use of pesticides in high doses resulted in maximal selection pressure for resistance and eliminated competing populations, actually accelerating the proliferation of resistant pest populations. In 2015, Barzman et al., on the basis of 50 years of agricultural experience, formalized the fundamental principles of integrated pest management that proved most successful in obtaining long-term control of pest populations. This chapter discusses these eight principles within the context of cancer biology and provides a novel qualitative framework to build and develop a long-term management paradigm for 118