In Vivo Efficacy of Multi-Targeted Androgen Inhibition as Prostate Cancer Therapy

项目概述：我的长期目标是从事转化研究，专注于前列腺癌的分子研究和临床治疗。我的近期职业目标是发展前列腺癌生物学和临床研究方面的专业知识，这将使我能够作为一名独立的医师调查员追求职业生涯。通过教学和指导研究经验的结合，我将在统计学，伦理学，前列腺肿瘤生物学和临床试验开发方面打下基础，这将使我能够申请并获得临床研究领域的资金，这些领域将从我目前对雄激素对前列腺上皮组织的分子作用的兴趣中发展出来。哈钦森中心和华盛顿大学的研究基础设施，前列腺孢子和前列腺癌研究项目创造的合作环境，以及我的导师提供的双重科学和临床指导，涵盖了我成功过渡到独立职业所需的所有资源。确定前列腺内雄激素水平是否可以被抑制到一个阈值以下，在这个阈值下，基本上所有的前列腺癌细胞都进行凋亡，从来没有定量地解决过。在这个提议中，我们将定量的雄激素降低治疗策略的药理学和治疗效果，通过测量前列腺内雄激素水平在肿瘤消退的组织和分子相关的背景下。患有局限性前列腺癌的男性将随机接受三个月的新辅助激素治疗，其中一种治疗旨在逐步抑制雄激素轴。在诊断和前列腺切除术中获得的前列腺样本将根据雄激素水平、组织反应的组织学测量和雄激素调节基因表达的评估来评估治疗效果。相关性：前列腺癌是美国男性中最常见的癌症，也是癌症相关死亡的第二大原因。前列腺癌细胞依靠激素睾丸激素生存。目前的激素治疗方法只能抑制睾丸激素的产生，最终无法控制前列腺癌细胞的生长。我们的研究将确定抑制多种睾酮来源（睾丸、肾上腺和前列腺）的治疗是否会比目前的方法更有效地降低前列腺内的激素水平，从而更有效地杀死前列腺癌细胞。

DESCRIPTION (provided by applicant): Project Summary: My long term goal is a career in translational research, focused on the molecular investigation and clinical treatment of prostate cancer. My immediate career goal is to develop the expertise in prostate cancer biology and clinical research that will allow me to pursue an independent career as a physician-investigator. Through a combination of didactics and mentored research experiences I will lay a groundwork in statistics, ethics, prostate tumor biology and clinical trial development that will position me to apply for and obtain funding in clinical research areas that will grow out of my current interests in the molecular effects of androgens on prostatic epithelial tissue. The research infrastructure of the Hutchinson Center and the University of Washington, the collaborative environment created by the Prostate SPORE and Program in Prostate Cancer Research, and the dual scientific and clinical mentorship provided by my mentors encompass all the resources I will need to successfully transition to an independent career. Establishing whether intraprostatic androgen levels can be suppressed to below a threshold at which essentially all prostate cancer cells undergo apoptosis has never been quantitatively addressed. In this proposal we will quantitative the pharmacologic and treatment efficacy of androgen lowering treatment strategies by measuring intraprostatic androgen levels in context of tissue and molecular correlates of tumor regression. Men with localized prostate cancer will be randomized to receive three months of neoadjuvant hormonal therapy with one of four treatments designed to progressively inhibit the androgen axis. Prostate samples obtained at diagnosis and prostatectomy will be assayed for treatment efficacy based on androgen levels, histological measures of tissue response, and assessment of androgen-regulated gene expression. Relevance: Prostate cancer is the most common cancer in American men, and the second leading cause of cancer-related death. Prostate cancer cells rely on the hormone testosterone for survival. Current methods of hormonal treatment only inhibit testicular hormone production, and ultimately fail to control the growth of prostate cancer cells. Our study will determine whether treatments inhibiting multiple sources of testosterone production (testicular, adrenal and prostatic) will be more effective than current methods in decreasing hormone levels inside the prostate, and therefore, more effective in killing prostate cancer cells.