Transcriptional Regulation of the Androgen Receptor in Prostate Cancer

摘要 本次K08职业发展奖支持的建议包括5年职业发展和 研究计划，将为David Takeda博士提供过渡到 独立调查员。武田医生是达纳医院泌尿生殖肿瘤科的讲师- 法伯癌症研究所，他的长期职业目标是成为一名专注于使用 功能基因组研究，以促进我们对前列腺癌的理解，以提供新的见解 变成了潜在的治疗方法。职业发展计划包括威廉·哈恩博士的指导，他是 他是功能基因组学领域的领军人物，并成功地指导了许多初级调查人员。至 进一步促进他的职业发展，导师计划包括与马修博士的合作 达纳-法伯癌症研究所的弗里德曼，他是研究前列腺癌的表观遗传学方法的先驱 癌症，以及由表观遗传学、类固醇激素等领域的领导者组成的咨询委员会 受体和癌症基因组学。这一研究方案的重点是理解一种新的机制。 前列腺癌中雄激素受体(AR)的调节。前列腺癌生存需要AR信号 雄激素靶向治疗是晚期疾病最有效的治疗方法。我们现在知道了， AR信号的恢复也是导致原发耐药发生和发展的主要机制 致命的抗去势前列腺癌，使AR成为抗去势的重要治疗靶点 疾病。尽管对AR信号的依赖，我们对AR本身是如何被调控的了解是有限的。 通过功能基因组和表观遗传学研究的结合，武田博士确定了一种新的增强剂 在前列腺癌中调节AR表达的元件。这项提案的总体研究计划是 确定这一发现对于理解前列腺癌AR生物学的意义。具体目标 包括：1)确定AR增强子在去势耐药疾病中的作用 在去势抵抗前列腺癌模型中激活AR增强子。2)阐明 HOXB13在AR增强子依赖性表达中的作用 学习。3)通过进行无偏功能遗传鉴定AR增强子的反式作用因子 屏幕上。在这项建议完成后，这些研究将证明AR增强剂的重要性 在前列腺癌进展中的作用并确定与增强子介导的转录有关的关键细胞因子 AR的控制。这些结果将极大地促进我们对AR监管的理解，并开辟新的 治疗干预的可能性。

ABSTRACT The proposal supported by this K08 Career Development Award consists of a 5-year career development and research plan that will provide Dr. David Takeda with the skills, experience, and mentorship to transition into an independent investigator. Dr. Takeda is an instructor in the Genitourinary Oncology Division at the Dana- Farber Cancer Institute whose long-term career goal is to become a physician-scientist focused on using functional genomic studies to advance our understanding of prostate cancer in order to provide new insights into potential therapeutics. The career development plan includes mentorship under Dr. William Hahn, who is a leader in the field of functional genomics and has successfully mentored numerous junior investigators. To further enhance his career development, the mentorship plan includes collaboration with Dr. Matthew Freedman at the Dana-Farber Cancer Institute who has pioneered epigenetic approaches to studying prostate cancer, and an advisory committee consisting of leaders in the fields of epigenetics, steroid hormone receptors, and cancer genomics. The focus of this research proposal is to understand a novel mechanism of regulation of the androgen receptor (AR) in prostate cancer. Prostate cancers require AR signaling for survival and androgen targeted therapies are the most effective treatment for advanced disease. We now know that restoration of AR signaling is also the principal mechanism driving primary resistance and development of lethal castrate resistant prostate cancer, making AR an important therapeutic target in castrate resistant disease. Despite this dependency on AR signaling, our knowledge of how AR itself is regulated is limited. Through a combination of functional genomic and epigenetic studies, Dr. Takeda identified a novel enhancer element that regulates AR expression in prostate cancer. The overall research plan of this proposal is to determine the significance of this finding for understanding the biology of AR in prostate cancer. Specific aims include: 1) To determine the contribution of the AR enhancer in progression to castrate resistant disease by activating the AR enhancer in models of castrate resistant prostate cancer. 2) To elucidate the role of HOXB13 in enhancer dependent expression of AR by using genome editing and mechanistic biochemical studies. 3) To identify trans-acting factors of the AR enhancer by performing an unbiased functional genetic screen. At the completion of this proposal, these studies will demonstrate the importance of the AR enhancer in prostate cancer progression and identify critical cellular factors involved in enhancer mediated transcriptional control of AR. These results will significantly advance our understanding of AR regulation and open up new possibilities for therapeutic intervention.