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De novo androgen synthesis as a mechanism contributing to the progression of prostate cancer to castration resistance Locke, Jennifer Ann

Abstract

Prostate cancer (CaP) is the leading cause of cancer in men affecting 24,700 Canadians each year and the third leading cause of cancer mortality with 4,300 deaths each year. CaP cells are derived from the prostate secretory epithelium and depend on androgen ligand activation of androgen receptor (AR) for survival, growth and proliferation. Androgen deprivation therapy (ADT) through pharmacological methods has been the leading form of CaP therapy since Huggin’s discovery that castration induced the regression of CaP tumors in 1941. Unfortunately, the cancer often recurs within 2-4 years in what has classically been considered “androgen-independent” (AI) disease. Growing evidence implicates androgens and AR activation in this disease recurrence despite castration, suggesting that this terminology should be more appropriately called “castration-resistant” prostate cancer (CRPC). Firstly, AR is found amplified, overexpressed or mutated in a majority of recurrent cancers as compared to primary cancers and secondly, intratumoral testosterone levels remain the same pre- and post-ADT. Additionally, the measured intratumoral DHT levels are sufficient to activate AR in recurrent CaP cells despite low serum androgen levels suggesting that intratumoral androgens remain important mediators of AR-mediated CaP progression. Previously, we and others discovered that recurrent tumor cells have elevated levels of enzymes in the pathways necessary for androgen synthesis from cholesterol. The central hypothesis in this thesis is that after ADT, CaP cells adapt to synthesize their own androgens for survival and proliferation. The goal of this PhD dissertation is to decipher the mechanisms whereby prostate tumor cells de novo synthesize androgens and how these events contribute to recurrent CaP. We show herein that CRPC tumor cells are capable of producing androgens and that upstream cholesterol and fatty acids are key mediators in this process. Furthermore, CRPC tumor cells adapt quickly to bypass current targeted therapies by utilizing multiple interlinked steroidogenesis pathways to continue to produce androgens necessary for AR activation. By understanding the mechanisms of intratumoral de novo androgen synthesis and how they contribute to CaP progression, more specific and effective therapeutics can be developed to treat this disease.

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