Mechanisms for the Transition to Castrate Resistant Prostate Cancer

向去势抵抗性前列腺癌转变的机制

• 批准号: 7796470
• 负责人: Stephen R. Plymate
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796470
• 关键词: Age; Androgen Receptor; Androgens; Animal Model; Biological Markers; Cancer Research Project; Castration; Data; Effectiveness; Enzymes; Epithelial Cells; Event; Exons; Fred Hutchinson Cancer Research Center; Gene Expression; Generations; Genetic Transcription; Growth; Health; Healthcare Systems; Histone Deacetylase Inhibitor; Length; Ligand Binding Domain; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Modeling; Mus; Production; Prostate; Prostatic Neoplasms; RNA Splicing; Recurrence; Regulation; Resistance; Role; Signal Transduction; Specimen; Staging; Time; Transcript; Transgenic Mice; Tumor Volume; Universities; Variant; Veterans; Washington; Work; autocrine; base; chromosome 5 loss; human disease; male; men; new therapeutic target; probasin; promoter; public health relevance; receptor; receptor expression; sound; tumor; tumor progression

DESCRIPTION (provided by applicant): A. Mechanisms for the transition to Castrate Resistant Prostate cancer Hypothesis: Following castration there is a decrease in prostate tumor volume and progression in animal models and human disease. However over time most tumors recur. The recurrence is associated with an increase in androgen regulated gene expression, increased androgen receptor expression, and ectopic production of androgens by prostate epithelial cells (1-3). Based on our preliminary data, we hypothesize that following castration there is an increase in the generation of splice variants of the androgen receptor that are missing all or part of the c-terminal ligand binding domain and are constitutively active. The specific variants we describe in the Work Accomplished have deletions of exons 5, 6, and 7 (AR del 5, 6, 7) or exons 5 and 6 (AR del 5, 6). These variant receptors are transcriptionally active in the absence of ligand and increase expression of genes necessary for androgen synthesis. When these events occur, generation of constitutively active AR and autocrine production of androgens, the tumor has successfully progressed to a castration-resistant state. In addition to the stimulation of androgen synthesis and AR transcription, the constitutively active AR suppresses IGF-IR gene expression. We hypothesize that inhibition of production or translocation of the AR and its splice variants will inhibit conversion to castrate resistant prostate cancer. Aim 1. Determine the timing of the increase in AR variants following castration and correlate the increase with the increase in wild-type AR, androgen synthesizing enzyme transcripts. Tumor measurements of androgens will be will be done in all specimens and correlated with splice variants, and synthesis enzyme expression. Aim 2. Determine the differences in gene expression when AR signaling is through the splice variant vs wt androgen ligated AR. Aim 3. Determine the role of splice variant ARs that increase following castration in the regulation of IGF-IR expression and the timing of effectiveness of histone deacetylase inhibitors or the inhibition of IGF-IR signaling on inhibition of prostate cancer growth as well as AR full length and variant expression. Aim 4. Determine the role of the AR-splice variant in progression of prostate cancer in an animal model. This aim will be started in year 1 and will require making a transgenic mouse expressing the AR 5, 6, 7 splice variant with a conditional probasin promoter. This mouse will be crossed with the TRAMP model of prostate cancer. The results of this study will define the role of constitutively active AR splice variants in the progression of prostate cancer following castration and effects of therapy targeting these variants. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common cancer in men including male veterans. It increases in men with age and thus will not appear from the veteran's health concerns. In the Puget Sound Health Care System (PSHCS) alone there are over 700 cases of prostate cancer in various stages of treatment, this proposal may define a new biomarker, AR del5, 6, 7 for men most likely to benefit from therapy of their prostate cancer as well as a new therapeutic target. The PSHCS has an active prostate cancer research program and collaborates with the University of Washington and Fred Hutchinson Cancer Research Center to develop better treatments for prostate cancer. This proposal should also shed significant new light on mechanisms of progression to the lethal form of prostate.

描述（由申请人提供）： A. 向去势抵抗性前列腺癌转变的机制 假设：去势后，动物模型和人类疾病中前列腺肿瘤体积和进展减少。然而随着时间的推移，大多数肿瘤会复发。复发与雄激素调节基因表达增加、雄激素受体表达增加以及前列腺上皮细胞异位产生雄激素有关 (1-3)。根据我们的初步数据，我们假设去势后雄激素受体剪接变体的产生增加，这些剪接变体缺失全部或部分c端配体结合结构域并且具有组成型活性。我们在已完成的工作中描述的具体变体删除了外显子 5、6 和 7 (AR del 5, 6, 7) 或外显子 5 和 6 (AR del 5, 6)。这些变异受体在没有配体的情况下具有转录活性，并增加雄激素合成所需基因的表达。当这些事件发生时，组成性活性 AR 的产生和雄激素的自分泌产生，肿瘤已成功进展到去势抵抗状态。除了刺激雄激素合成和 AR 转录外，组成型活性 AR 还抑制 IGF-IR 基因表达。我们假设抑制 AR 及其剪接变体的产生或易位将抑制向去势抵抗性前列腺癌的转化。目标 1. 确定去势后 AR 变异增加的时间，并将这种增加与野生型 AR、雄激素合成酶转录本的增加联系起来。将在所有样本中进行雄激素的肿瘤测量，并将其与剪接变体和合成酶表达相关联。目标 2. 确定通过剪接变体与野生型雄激素连接 AR 进行 AR 信号传导时基因表达的差异。目标 3. 确定去势后增加的剪接变体 AR 在 IGF-IR 表达调节中的作用以及组蛋白脱乙酰酶抑制剂的有效性时间或抑制 IGF-IR 信号传导对抑制前列腺癌生长以及 AR 的充分作用长度和变体表达。目标 4. 在动物模型中确定 AR 剪接变体在前列腺癌进展中的作用。该目标将于第一年开始，需要制作表达带有条件性探针启动子的 AR 5、6、7 剪接变体的转基因小鼠。这只小鼠将与前列腺癌的 TRAMP 模型杂交。这项研究的结果将定义组成型活性 AR 剪接变体在去势后前列腺癌进展中的作用以及针对这些变体的治疗效果。 公共卫生相关性： 前列腺癌是男性（包括男性退伍军人）中最常见的癌症。它在男性中随着年龄的增长而增加，因此不会出现退伍军人的健康问题。仅在普吉特湾医疗保健系统 (PSHCS) 就有超过 700 例前列腺癌病例处于不同的治疗阶段，该提案可能会为最有可能从前列腺治疗中受益的男性定义一个新的生物标志物 AR del5, 6, 7癌症以及新的治疗靶点。 PSHCS 拥有一项活跃的前列腺癌研究计划，并与华盛顿大学和 Fred Hutchinson 癌症研究中心合作，开发更好的前列腺癌治疗方法。该提议还应该为前列腺致命形式的进展机制提供重要的新线索。