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De Novo Androgen Synthesis As a Mechanism Contributing to the Progression of Prostate Cancer to Castration Resistance

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De Novo Androgen Synthesis As a Mechanism Contributing to the Progression of Prostate Cancer to Castration Resistance DE NOVO ANDROGEN SYNTHESIS AS A MECHANISM CONTRIBUTING TO THE PROGRESSION OF PROSTATE CANCER TO CASTRATION RESISTANCE by JENNIFER ANN LOCKE B.Sc., The University of British Columbia, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2009 © Jennifer Ann Locke, 2009 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. ii Table of contents Abstract ...................................................................................................................................... ii Table of contents ....................................................................................................................... iii List of tables .............................................................................................................................. vi List of figures ........................................................................................................................... vii List of abbreviations ................................................................................................................ viii Acknowledgements .................................................................................................................. xii Dedication ............................................................................................................................... xiv Co-authorship statement ........................................................................................................... xv CHAPTER 1: Literature review, hypothesis and specific aims .................................................... 1 1.1 Androgen action in the prostate ......................................................................................... 1 1.1.1 Biology, origin and function of the prostate ................................................................ 1 1.1.2 Steroids and androgens ............................................................................................... 5 1.1.3. Androgen production- the hypothalamic-pituitary-gonadal axis ................................. 6 1.1.4 Androgen synthesis in the human ............................................................................... 7 1.1.4.1 Enzymes ............................................................................................................... 7 1.1.4.2 Androgen synthesis pathway ................................................................................. 9 1.1.5 Androgen action in the prostate ................................................................................ 11 1.1.6 Androgen receptor .................................................................................................... 12 1.2 Prostate cancer (CaP) ...................................................................................................... 14 1.2.1 Development of CaP ................................................................................................. 14 1.2.2 Epidemiology ........................................................................................................... 15 1.2.3 Diagnosis.................................................................................................................. 17 1.2.4 Role of androgens and the AR in the development of CaP ........................................ 18 1.2.5 CaP stages ................................................................................................................ 19 1.2.6 Current treatments for CaP ....................................................................................... 20 1.2.6.1 Localized therapies ............................................................................................. 20 1.2.6.2 Systemic therapies .............................................................................................. 21 1.2.6.3 Therapies for late-stage castration-resistant CaP ................................................. 23 1.3 Molecular basis for the development of castration-resistant prostate cancer (CRPC) ....... 24 1.3.1 Selected outgrowth of pre-existing androgen-independent lurker CaP cells ............... 26 1.3.2 Upregulation of anti-apoptotic survival pathways ..................................................... 26 1.3.3 Activation of growth factor pathways ....................................................................... 27 1.3.4 Increased hypersensitivity of AR to low levels of androgen ...................................... 28 1.3.5 Increased mutations in AR leading to promiscuous activation by other ligands ......... 29 1.3.6 Role of AR in progression to CRPC.......................................................................... 29 1.3.7 Potential role of ligand-mediated activation of AR in CRPC progression .................. 30 1.4 Increased lipogenesis in CRPC progression and its potential role in androgen synthesis .. 31 1.4.1 Sterol regulatory element binding proteins ................................................................ 32 1.4.2 Cholesterol in CaP .................................................................................................... 34 1.4.3 Fatty acids in CaP ..................................................................................................... 37 1.5 Evidence suggesting de novo androgen synthesis as a potential mechanism contributing to CRPC progression ............................................................................................................ 39 1.5.1 Potential role for fatty acids and cholesterol in de novo androgen synthesis in CaP cells .................................................................................................................................. 39 iii 1.5.2 Indirect evidence of steroidogenesis enzymes involvement in androgen synthesis during CRPC progression .................................................................................................. 39 1.6 Scope of thesis ................................................................................................................ 44 1.6.1 Hypotheses ............................................................................................................... 44 1.6.2 Rationale and specific aims ...................................................................................... 44 1.7 References ...................................................................................................................... 49 CHAPTER 2: Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer .................................................................... 67 2.1 Introduction .................................................................................................................... 67 2.2 Materials and methods .................................................................................................... 70 2.3 Results ............................................................................................................................ 74 2.4 Discussion......................................................................................................................
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