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: 8391557
• 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/8391557
• 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; 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; prostate cancer model; 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.

描述(由申请人提供)： 答：转变为抗去势前列腺癌假说的机制：在去势后，动物模型和人类疾病中的前列腺癌体积和进展都有所减少。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异体的产生增加，这些剪接变异体缺失全部或部分c末端配体结合域，并具有结构性活性。我们在已完成的工作中描述的特定变体有外显子5、6和7(AR del 5、6、7)或外显子5和6(AR del 5、6)的缺失。这些变异的受体在缺乏配体的情况下转录活跃，并增加雄激素合成所需基因的表达。当这些事件发生时，结构性活性AR的产生和雄激素的自分泌产生，肿瘤已经成功地进展到去势抵抗状态。除了刺激雄激素合成和AR转录外，结构性活性AR还抑制IGF-IR基因的表达。我们假设，抑制AR及其剪接变异体的产生或易位将抑制向去势耐药前列腺癌的转化。目的1.确定去势后AR变异体增加的时间，并将这种增加与野生型AR-雄激素合成酶转录物的增加相关联。将在所有样本中进行雄激素的肿瘤测量，并与剪接变异体和合成酶表达相关联。目的2.确定AR信号通过剪接变异体与雄激素连接的AR时基因表达的差异。目的3.确定去势后增加的剪接变异体ARs在调节IGF-IR表达中的作用，以及组蛋白脱乙酰酶抑制剂或抑制IGF-IR信号抑制前列腺癌生长以及AR全长和变体表达的时机。目的4.在动物模型中确定AR-Splice变异体在前列腺癌进展中的作用。这个目标将在第一年开始，需要制造一只表达AR5、6、7剪接变异体的转基因小鼠，并有条件地启动前盆。这只小鼠将与前列腺癌的TRAMP模型杂交。这项研究的结果将确定结构性活性AR剪接变异体在去势后前列腺癌进展中的作用以及针对这些变异体的治疗效果。