Modes of Prostate Ca Progression--role of p53 Pathway

描述：（改编自研究者摘要）过去十年 转移性前列腺癌夺去了40多万美国男性的生命， 在20001年仍然是美国男性癌症死亡的第二大常见原因。的 前列腺癌转移的分子基础知之甚少， 很少在人转移性前列腺癌细胞中进行研究，这些细胞直接来源于 患有这种疾病的患者。此外，增加的分子基础 非裔美国人前列腺癌的发病率和预后较差 不确定我们假设上游和下游效应子的改变 p53基因的功能，以及p53基因本身，是重要的贡献者， 前列腺癌进展。这一假设将通过两个测试 具体目标：具体目标1将检查p53通路的关键成员 (p53、小窝蛋白-1、p14、p21、MDM 2和ATM）在一系列143 雄激素依赖性和雄激素非依赖性骨、淋巴结和内脏 81例患者转移。结合分子分析技术 将确定1）是否发生p53通路改变的均匀模式， 来自个体患者的多个转移部位的样品和2）是否 特定的变化模式与特定的 前列腺癌的扩散（例如，仅骨vs骨+内脏 网站）。确定的信息量最大的分子技术将用于 检查前列腺癌初期切除的组织 从81例患者中的30例子集中获得诊断，以了解 这条途径改变的时机。其他分析将比较 将基因组杂交数据与p53途径数据平行比较 样本，以确定与特定缺陷相关的收益或损失 在p53通路中。具体目标2将测试假设，根据最近 发表的数据2 '3，p53改变模式的变化 前列腺癌的侵袭性增加可能是由于 非裔美国人结果来自31个雄激素依赖和 来自非洲裔美国人的雄激素非依赖性转移性前列腺癌， 在该分析中与来自50名白色和西班牙裔患者的样品进行比较。的 这些研究的结果将1）对未来的选择产生直接影响， 为前列腺癌患者提供的基因治疗和其他治疗，2） 将有助于评估肿瘤模型的相关性，其中p53失活是一个 关键因素，3）将有助于确定所需的基因组数据元素， 定义前列腺癌表型。

DESCRIPTION: (Adapted from the investigator's abstract) In the past ten years metastatic prostate cancer killed more than 400,000 American men and today remains the second most common cause of cancer death in U.S. men in 20001. The molecular basis of prostate cancer metastasis is poorly understood and has been rarely studied in human metastatic prostate cancer cells derived directly from patients with this disease. Moreover, the molecular basis for the increased incidence and poorer prognosis for prostate cancer in African-Americans remains uncertain. We hypothesize that alterations of upstream and downstream effectors of p53 gene function, and of the p53 gene itself, are important contributors to prostate cancer progression. This hypothesis will be tested through two specific aims: Specific Aim 1 will examine critical members of the p53 pathway (p53, Caveolin-l, p14, p21, MDM2, and ATM) in a series of 143 androgen-dependent and androgen-independent bone, lymph node, and visceral metastases from 81 patients. A combination of molecular analysis techniques will determine 1) whether uniform patterns of p53 pathway alteration occur in samples from multiple metastatic sites from individual patients and 2) whether specific patterns of alteration are associated with specific modes of dissemination of prostate cancer (e.g., bone only versus bone plus visceral sites). The most informative molecular techniques identified will be used to examine prostate cancer tissue removed at the time of initial prostate cancer diagnosis from a subset of 30 of the 81 total patients to provide insight into the timing of alteration of this pathway. Additional analysis will compare comparative genomic hybridization data to the p53 pathway data in parallel specimens to identify gains or losses that are associated with specific defects in the p53 pathway. Specific Aim 2 will test the hypothesis, based on recently published data2'3, that variations in the pattern of alteration of the p53 pathway may account for increased aggressiveness of prostate cancer in African-Americans. Results from a subset of 31 androgen-dependent and androgen-independent metastatic prostate cancers from African-Americans will be compared to samples from 50 White and Hispanic patients in this analysis. The results of these studies will 1) have a direct impact on future selection of gene therapy and other therapies offered to patients with prostate cancer, 2) will help evaluate the relevance of tumor models in which p53 inactivation is a critical factor, and 3) will help identify genomic data elements needed to define prostate cancer phenotypes.