Biology of the Prostate Cancer Prevention Trial (PCPT)

前列腺癌预防试验 (PCPT) 的生物学

• 批准号: 6907173
• 负责人: SCOTT M LIPPMAN
• 金额: $ 259.14万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907173
• 关键词: cancer prevention; chemoprevention; human data; meta analysis; prostate neoplasms

Prostate cancer is the most frequent non-skin cancer, the second leading cause of cancer death in U.S. men, and is increasing in incidence. Effective prevention requires a better understanding of the etiology of prostate cancer, a major goal of this P01's biological studies of the historical Prostate Cancer Prevention Trial (PCPT). A randomized, controlled trial of finasteride in 18,882 men, the PCPT found a 24.8% decrease in overall prostate cancer risk and an apparently increased risk of high-grade disease (New England Journal of Medicine [NEJM], July 2003). Prostate cancer is an androgen-dependent disease, and finasteride inhibits 5a-reductase, thus blocking the conversion of testosterone (by 5a-reductase) to dihydrotestosterone, the most active prostate androgen. The five proposed highly interactive P01 studies of the PCPT are: Project 1, Androgen Metabolism; Project 2, Diet and Diet-Related Factors; Project 3, Insulin-like Growth Factor Axis and Insulin Resistance; Project 4, Genotypic and Phenotypic Studies of Inflammation; and Project 5, Oxidative Damage and DNA Repair. These projects will use nested case (n=1800)-control (n=1800) designs to develop the P01 theme, which is the genetic, metabolic and environmental factors associated with the risk of prostate cancer overall or high-grade disease and the effects of these factors on finasteride preventive efficacy. The mechanisms underlying these risk-factor associations also will be assessed. Major elements of the P01 theme are the study (1) of genetic polymorphisms to identify molecular prostate cancer risk factors and determine pharmacogenetic profiles and (2) of somatic mutations to discover the mechanisms underlying increased high-grade prostate cancer risk associated with finasteride. The P01 provides each project access to the invaluable repository of PCPT biospecimens and data. Each project is closely linked by interactive specific aims and planned collaborations with the other 4 projects and 3 cores. Unique P01 strengths include its biopsy-confirmed control group, the value of which is underscored by PCPT data indicating a substantial prevalence of cancer and high-grade disease in men with "normal" prostate-specific antigen and digital rectal exam (NEJM, May 2004), and standard centralized histological classifications. With fully clarified interactions and a large amount of highly relevant new preliminary data, this resubmitted P01 promises to develop comprehensive prostate cancer risk models important to the future study and prevention of prostate cancer.

前列腺癌是最常见的非皮肤癌，是美国男性癌症死亡的第二大原因，并且发病率正在上升。有效的预防需要更好地了解前列腺癌的病因，这是历史性前列腺癌预防试验 (PCPT) 的 P01 生物学研究的主要目标。 PCPT 对 18,882 名男性进行了一项非那雄胺随机对照试验，发现总体前列腺癌风险降低了 24.8%，并且严重疾病的风险明显增加（新英格兰医学杂志 [NEJM]，2003 年 7 月）。前列腺癌是一种雄激素依赖性疾病，非那雄胺抑制 5a-还原酶，从而阻止睾酮（通过 5a-还原酶）转化为最活跃的前列腺雄激素二氢睾酮。 PCPT 提出的五项高度互动的 P01 研究是： 项目 1，雄激素代谢；项目2，饮食和饮食相关因素；项目3，类胰岛素 生长因子轴和胰岛素抵抗；项目4，炎症的基因型和表型研究；以及项目 5，氧化损伤和 DNA 修复。这些项目将使用嵌套病例（n=1800）-对照（n=1800）设计来开发P01主题，即与前列腺癌总体或高级别疾病风险相关的遗传、代谢和环境因素以及这些因素对非那雄胺预防功效的影响。这些风险因素关联的潜在机制也将被评估。 P01 主题的主要内容是研究 (1) 遗传多态性研究，以识别分子前列腺癌风险因素并确定药物遗传学特征；(2) 体细胞突变研究，以发现与非那雄胺相关的高级别前列腺癌风险增加的机制。 P01 使每个项目都能访问宝贵的 PCPT 生物样本和数据存储库。每个项目都通过互动的具体目标以及与其他 4 个项目和 3 个核心的计划合作紧密相连。 P01 的独特优势包括其活检证实的对照组，PCPT 数据强调了其价值，表明前列腺特异性抗原和直肠指检“正常”的男性中癌症和重度疾病的患病率很高（NEJM，2004 年 5 月），以及标准的集中组织学分类。凭借完全阐明的相互作用和大量高度相关的新初步数据，重新提交的 P01 有望开发出对前列腺癌未来研究和预防非常重要的全面前列腺癌风险模型。