AR signaling in Hormone Refractory Prostate Cancer

描述（由申请人提供）： 雄激素受体（AR）介导前列腺中的雄激素信号传导，并在前列腺癌发展的所有阶段（包括最终的雄激素非依赖性阶段）中发挥重要作用。体细胞AR突变、AR表达增加、AR辅激活因子表达增加和/或AR雄激素非依赖性活性都是导致前列腺癌进展为雄激素非依赖性疾病的潜在机制。这种异常的AR活性可能影响和/或预测激素消融治疗失败的时间。由于目前的临床实践并没有考虑这些机制的选择或治疗时机，我们建议使用积极的化疗和/或替代雄激素消融治疗结合失败的潜在机制的知识。我们认为，对化疗或替代性激素消融治疗的反应将受到原始消融治疗失败的潜在AR机制的影响。在具体目标#1中，我们将测量代表不同疾病阶段的队列中男性存档组织中的AR突变和AR、p160共激活因子和HER 2的表达水平。在具体目标#2中，我们打算在小鼠中使用CWR 22肿瘤模型进行临床前试验，以测试早期治疗以及它如何与雄激素消融治疗过程中生物学选择的特定分子异常相关。总的来说，我们的工作将提供激素抵抗性前列腺癌的分子框架，预后的重要指标，以及未来几项雄激素非依赖性前列腺癌替代治疗策略的临床试验的基础。

DESCRIPTION (provided by applicant): The androgen receptor (AR) mediates androgen signaling in the prostate and plays a vital role during all phases of prostate cancer development including the final androgen-independent phases. Somatic AR mutations, increased AR expression, increased AR coactivator expression and/or AR androgen-independent activity are all potential mechanisms causing prostate cancer progression to androgen-independent disease. Such aberrant AR activities might affect and/or predict time to hormone ablation therapy failure. Since clinical practice at present does not consider these mechanisms in choice or timing of treatment, we propose the use of aggressive chemotherapy and/or alternative androgen ablation treatments in conjunction with knowledge of the underlying mechanism of failure. We propose that response to chemo- or alternative hormone ablation therapy will be affected by the underlying AR mechanism of the original ablation therapy failure. In specific aim #1, we will measure AR mutations and expression levels of AR, p160 coactivators and HER2 in archival tissue from men in cohorts representing different stages of disease. In specific aim #2, we intend to do a preclinical trial using the CWR22 tumor model in mice to test early therapy and how it relates to the particular molecular abnormality biologically selected for during the course of androgen ablation treatment. Overall our work will provide a molecular framework of hormone resistant prostate cancer, important indices of prognosis, and the basis for several future clinical trials in alternative treatment strategies of androgen-independent prostate cancer.