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.过渡到castrate抗性前列腺癌假设的机制：cast割后，动物模型和人类疾病的前列腺肿瘤体积和进展下降。但是随着时间的流逝，大多数肿瘤都会复发。复发与雄激素调节基因表达的增加有关，雄激素受体表达增加以及前列腺上皮细胞对雄激素的异位产生（1-3）。基于我们的初步数据，我们假设cast割后，雄激素受体的剪接变体的产生增加，而雄激素受体的剪接变体缺少全部或部分C-末端配体结合结构域，并且具有组成性活性。我们在完成的工作中描述的特定变体具有外显子5、6和7（ar del 5、6、7）或外显子5和6（Ar del 5、6）的缺失。这些变体受体在没有配体的情况下具有转录活性，并增加了雄激素合成所需的基因表达。当这些事件发生时，雄激素的组成型活性AR和自分泌产生的产生，肿瘤已成功发展为cast割的状态。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的产生或易位及其剪接变异将抑制转化为castrate抗性前列腺癌。 AIM 1。确定cast割后AR变体增加的时机，并将其与野生型AR，雄激素合成酶转录物的增加相关。将在所有标本中进行雄激素的肿瘤测量结果，并与剪接变体和合成酶表达相关。 AIM 2。确定AR信号通过剪接变体与WT雄激素结扎的AR时的基因表达差异。 AIM 3。确定剪接变体AR的作用，这些ARS在cast割后增加了IGF-IR表达调节以及组蛋白脱乙酰基酶抑制剂有效性的时间或IGF-IR信号抑制对抑制前列腺癌生长以及AR全长和变异表达的抑制。 AIM 4。确定AR-Splice变体在动物模型中前列腺癌进展中的作用。这个目标将在第1年开始，并需要制作带有条件探针启动子的AR 5、6、7剪接变体的转基因小鼠。该小鼠将与前列腺癌的流浪汉模型交叉。这项研究的结果将定义cast割和针对这些变异的治疗后，组成性活性AR剪接变异在前列腺癌进展中的作用。 公共卫生相关性： 前列腺癌是包括男性退伍军人在内的男性中最常见的癌症。随着年龄的增长，它会增加，因此不会出于退伍军人的健康问题而出现。仅在普吉特海湾医疗保健系统（PSHC）中，在各种治疗阶段就有700例前列腺癌病例，该提案可能会定义一种新的生物标志物，Ar del5、6、7的男性，最有可能受益于其前列腺癌的治疗以及新的治疗靶标。 PSHCS拥有一项活跃的前列腺癌研究计划，并与华盛顿大学和弗雷德·哈钦森癌症研究中心合作，为前列腺癌开发更好的治疗方法。该提议还应该为进展到致命形式的前列腺的机制提供重大新的启示。