ANDROGEN RECEPTOR ANALYSIS IN REFRACTORY PROSTATE CANCER

描述：(申请人的描述)前列腺癌的发病率是 每年都在增加，预计1997年将有41900人死亡 死于前列腺癌。最初，大多数患有前列腺癌的男性 可以通过从系统中去除睾丸素来成功治疗。 然而，在中位数18个月后，这种疾病就变成了雄激素 独立，在缺乏睾丸素的情况下开始再生。一个很长的 本项目的学期目标是研究黄曲霉毒素的分子机制。 雄激素独立性。这个项目的重点将是雄激素。 受体。雄激素受体调节正常前列腺细胞的生长 以及前列腺癌。在前列腺癌中，雄激素的突变 已在雄激素非依赖性前列腺癌中发现受体，但 罕见的早期激素敏感型癌症。突变体的功能研究 雄激素受体已经显示突变的受体有不同的结合 激素和激素拮抗剂的亲和力和特异性。在……里面 尤其是前列腺癌拮抗剂羟基氟他胺 刺激一些突变的受体。此外，还观察到， 一些患者会对停药有临床反应。 抗雄激素治疗。因此，检查流行率是很重要的。 以及雄激素受体突变的类型，并确定它们在 前列腺癌的自然病史。 该项目的第一个目标是评估 晚期雄激素患者肿瘤中雄激素受体突变的研究 独立型前列腺癌。前列腺癌样本将从 登记为B组癌症和白血病患者的骨髓活检 旨在研究单独停用抗雄激素的试验或 停用抗雄激素联合肾上腺激素阻断。这 试验将提供230个可能获得肿瘤的骨髓样本 检查雄激素受体的序列。额外的120根骨头 骨髓样本将在第二年从患者身上获得 参加二次口服抗雄激素治疗的后续试验。 该项目的第二个目标是评估两者之间的联系 受体突变与临床结局，包括生存和对 二次口服抗雄激素治疗的反应和停用抗雄激素药物。 人们希望对雄激素分子变化的了解 与临床相关的受体可能提供对进展的洞察 并导致更持久的荷尔蒙疗法。

DESCRIPTION: (Applicant's Description) The incidence of prostate cancer is increasing annually and, in 1997, it is expected that 41,900 men will die from prostate cancer. Initially, the majority of men with prostate cancer can be treated successfully by removing testosterone from the system. However, after a median of 18 months, the disease becomes androgen independent and starts to regrow in the absence of testosterone. A long term objective of this project is to study the molecular mechanisms of androgen independence. The focus of this project will be on the androgen receptor. The androgen receptor regulates growth in normal prostate cells and in prostate cancer. In prostate cancer, mutations in the androgen receptor have been found in androgen independent prostate cancer but are rare in early stage hormone sensitive cancer. Functional studies of mutant androgen receptors have shown that mutant receptors have different binding affinities and specificities for hormones and hormone antagonists. In particular, the prostate cancer antagonist hydroxyflutamide actually stimulates some mutant receptors. In addition, it has been observed that some patients will have a clinical response to discontinuation of antiandrogen therapy. It is important, therefore, to examine the prevalence and type of androgen receptor mutations and identify their importance in the natural history of prostate cancer. The first aim of this project is to evaluate the frequency and type of androgen receptor mutations in tumors from patents with advanced androgen independent prostate cancer. Prostate tumor sample will be obtained from bone marrow biopsies of patients enrolling on a Cancer and Leukemia Group B trial designed to study the withdrawal of antiandrogen alone or the withdrawal of antiandrogen combined with adrenal hormone blockade. This trial will provide 230 bone marrow samples from which tumor may be obtained to examine the sequence the androgen receptor. An additional 120 bone marrow samples will be obtained during the second year from patients enrolling on a successor trial of secondary oral antiandrogen therapy. The second aim of this project is to evaluate the association between receptor mutations and clinical outcomes, including survival and response to antiandrogen withdrawal and response to secondary oral antiandrogen therapy. It is hoped that an understanding of molecular changes in the androgen receptor with clinical correlation may provide insight into the progression of androgen independence and lead to more durable hormonal therapies.