Androgen Signaling in prostate cancer progression and CRPC development

前列腺癌进展和 CRPC 发展中的雄激素信号传导

• 批准号: 9197890
• 负责人: ZIJIE SUN
• 金额: --
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197890
• 关键词: Ablation; Address; Androgen Receptor; Androgens; Animal Model; Biological; Biological Models; Bypass; Cell Differentiation process; Cell Proliferation; Cells; Clinical; Data; Development; Disease; Disease Progression; ETS Family Protein; ETV1 gene; Environment; Future; Gene Amplification; Gene Expression Profiling; Gene Targeting; Genes; Growth; Hormones; Human; Intervention; Lead; Ligands; Light; Malignant neoplasm of prostate; Mediating; Molecular; Mouse Strains; Neoplasm Metastasis; Nuclear Hormone Receptors; Oncogenic; Patients; Process; Property; Prostatic Neoplasms; Receptor Activation; Refractory; Relapse; Reporter; Role; Signal Pathway; Signal Transduction; Stanolone; Testing; Testosterone; Transgenic Mice; Transgenic Organisms; Tumor Initiators; androgen deprivation therapy; androgen sensitive; cancer initiation; castration resistant prostate cancer; cell growth; effective therapy; mortality; mouse model; novel; novel therapeutic intervention; prostate cancer cell; prostate carcinogenesis; public health relevance; therapeutic target; tumor progression

DESCRIPTION (provided by applicant): The androgen receptor (AR) is a nuclear hormone receptor and promotes prostate cancer growth through activation of its downstream target genes. Although the targets of AR activation remain unclear, they are believed to be critical for cellular proliferation because most prostate cancers express the AR and are androgen-dependent. That depletion of androgens results in significant regression of prostate tumors was demonstrated in 1941 by Charles Huggins and Clarence Hodges and heralded what is now the ubiquitous strategy of androgen deprivation therapy to treat prostate cancer. Unfortunately, within two to three years after initiating therapy, most patients invariably relapse with a more aggressive form of prostate cancer, known as castration resistant prostate cancer (CRPC). There is no effective treatment option for CRPC, which has mainly contributed to the mortality of the disease. AR gene amplification has been observed in almost one-third of prostate cancers after androgen ablation therapy. Global gene expression profiling shows AR as the only gene to be consistently up-regulated in CRPC, implicating the significance of AR in disease progression. We and others have provided multiple lines of evidence demonstrating a critical role of AR in ligand-independent cell growth, implying that androgen- independent cells may still be "AR dependent" and that the AR can be used as a possible therapeutic target. However, the precise role of the AR in prostate cancer progression and CRPC development is still unclear. One of the main reasons for the limited progress is the lack of appropriate animal models that can be used to evaluate ligand independent AR action during the course of disease progression. To address this, we have developed several novel mouse models that allow us to investigate the progression of prostate cancer that is androgen independent but AR-dependent, mimicking what typically occurs in most human prostate cancers. In this competing renewal, we propose three different but integrated specific aims to directly test our central hypothesis that abnormal activation of AR dysregulates cell differentiation and proliferation that directly contribute to prostate cancer initiation and progression. Three specific aims are proposed in this application to address three different but related questions: 1) how abnormal activation of AR promotes tumor progression? 2) does aberrant activation of AR induce expression and activation of ETS proteins in promoting prostate cancer progression? 3) what are the molecular mechanisms underlying aberrant activation of AR in prostate cancer progression and CRPC development?

描述（由申请人提供）：雄激素受体（AR）是一种核激素受体，并通过激活其下游靶基因促进前列腺癌的生长。尽管AR激活的靶标仍然不清楚，但人们认为它们对于细胞增殖至关重要，因为大多数前列腺癌表达AR并且依赖于雄激素。 1941年，查尔斯·哈金斯（Charles Huggins）和克拉伦斯·霍奇斯（Clarence Hodges）证明了雄激素的耗竭导致前列腺肿瘤的显着消退，并预示了现在的雄激素剥夺治疗的普遍存在策略，以治疗前列腺癌。不幸的是，在开始治疗后的两到三年内，大多数患者总是会以更具侵略性的前列腺癌（称为耐castatration抗性前列腺癌（CRPC））复发。 CRPC没有有效的治疗选择，这主要导致该疾病的死亡率。 在雄激素消融疗法后，几乎三分之一的前列腺癌中已经观察到了AR基因扩增。全球基因表达分析表明，AR是CRPC中唯一一贯上调的基因，这暗示了AR在疾病进展中的重要性。我们和其他人提供了多种证据，证明了AR在非配体无依赖性细胞生长中的关键作用，这意味着雄激素独立细胞可能仍然是“依赖性的”，并且可以将AR用作可能的治疗靶标。但是，AR在前列腺癌进展和CRPC发展中的确切作用尚不清楚。进步有限的主要原因之一是缺乏适当的动物模型，这些模型可用于在疾病进展过程中评估配体独立AR作用。为了解决这个问题，我们开发了几种新型的小鼠模型，使我们能够研究独立但依赖AR的前列腺癌的进展，并模仿大多数人类前列腺癌中通常发生的情况。在这种竞争的更新中，我们提出了三种不同但综合的特定目的，旨在直接检验我们的中心假设，即AR异常激活的细胞分化和增殖直接导致前列腺癌的启动和进展。在本应用中提出了三个具体目标，以解决三个不同但相关的问题：1）AR异常激活如何促进肿瘤进展？ 2）AR的异常激活是否诱导ETS蛋白的表达和激活在促进前列腺癌进展中？ 3）在前列腺癌进展和CRPC发展中，AR的异常激活的基本机制是什么？