A study of two major challenges in prostate cancer : effective chemo-prevention and overcoming resistance to hormonal and chemotherapy

Abstract: For men, over the course of a lifetime the risk of developing prostate cancer is 1 in 9. Both the illness itself and treatment affect quality of life in multiple aspects, including urinary problems, pain, and sexual dysfunction. Current clinical challenges in this field include: inevitable drug resistance to treatments, lack of accurate diagnostic and prognostic biomarkers, as well as no common chemoprevention strategies. The aim of this thesis is therefore to identify transcript alternations associated with drug resistance (Study I and Study II), to evaluate potential drug targets for prostate cancer treatment (Study III), and to estimate the preventive effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) against prostate cancer (Study IV). Castration resistance and docetaxel resistance are two significant issues that arise during prostate cancer disease progression. We employed next generation RNA sequencing technology to compare hormone-resistant (Study II) and docetaxel-resistant (Study I) vs respective sensitive cell lines, aiming to discover a potential drug target with the capability of prolonging the duration of hormone and docetaxel treatments before the cancer cells becoming resistant. The results showed that a variety of transcript alterations were obtained during resistance development, including mutations, altered gene expressions, and fusion transcripts. These alterations might be associated with drug resistance in prostate cancer. As a rationale for Study III, we hypothesized that proteins that have never been reported as mutated in prostate cancer might play an important role in cancer progression through their essential function of maintaining cellular stability in cancer cells. Upon mutation, these genes would induce severe cellular instability such that the cells could not survive, and these cells would be erased through natural selection during cancer growth. In Study III, we therefore evaluated a non-mutated protein in prostate cancer, GPR89A, as a potential drug target with possible anti-cancer function. Low-dose aspirin has been recommended by the U.S. Preventive Services Task Force (USPSTF) to prevent cardiovascular disease and colorectal cancer. However, results published in scientific studies are controversial regarding prostate cancer. In Study IV, we assessed whether maintenance use of aspirin or other NSAIDs could reduce the risk of prostate cancer. Based on data from the Swedish Cancer Register, the Swedish Prescribed Drug Register and the Swedish Causes of Death Register (2005-2012), we conducted a nationwide cohort study and found a protective effect of aspirin and other NSAIDs against prostate cancer, especially after long-term intake. In sum, this thesis identified or assessed alternative methods against prostate cancer through exploring molecular approaches to develop more effective treatment methods, and by attempting to reduce the prevalence of cancer cases through chemoprevention.

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