ANDROGEN RECEPTOR ANALYSIS IN REFRACTORY PROSTATE CANCER

描述：（申请人的描述）前列腺癌的发病率是 每年增加，1997年预计将有41，900人死亡， 得了前列腺癌 最初，大多数前列腺癌患者 可以通过去除体内的睾丸激素来成功治疗 然而，在中位数18个月后， 在没有睾丸激素的情况下开始再生。 很长 本项目的长期目标是研究 雄激素非依赖性 这个项目的重点将是雄激素 受体的 雄激素受体调节正常前列腺细胞的生长 和前列腺癌。 在前列腺癌中， 受体在雄激素非依赖性前列腺癌中被发现， 在早期激素敏感性癌症中罕见。 突变体的功能研究 雄激素受体已经表明突变的受体具有不同的结合 对激素和激素拮抗剂的亲和力和特异性。 在 特别是前列腺癌拮抗剂羟氟沙星， 刺激一些突变受体 此外，据观察， 一些患者会对停止治疗有临床反应， 抗雄激素治疗 因此，重要的是检查 和雄激素受体突变的类型，并确定其在 前列腺癌的早期症状 本项目的第一个目的是评估 晚期雄激素患者肿瘤中雄激素受体突变的研究 独立的前列腺癌。 前列腺肿瘤样本将从 入组癌症和白血病组B的患者的骨髓活检 试验旨在研究单独停用抗雄激素或 停用抗雄激素联合肾上腺激素阻断。 这 试验将提供230份骨髓样本，从中可能获得肿瘤 检测雄激素受体的序列 额外的120块骨头 第二年将从患者中采集骨髓样本 正在参加一项二级口服抗雄激素治疗的后续试验 本项目的第二个目的是评估 受体突变和临床结局，包括生存率和对 抗雄激素戒断和对二次口服抗雄激素治疗的反应。 希望对雄激素分子变化的理解 受体与临床相关性可能提供深入了解进展 雄激素不依赖性，并导致更持久的激素治疗。

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.