BIOSTATISTICS/ADMINISTRATIVE

生物统计/行政

基本信息

批准号：
7254404
负责人：
CLEMENT C IP
金额：
$ 8.83万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254404
关键词：
Address Androgen Receptor Androgen Suppression Androgens Apoptosis Binding Biometry Cancer Control Caring Caspase Clinical Clinical Trials Clonal Expansion Complex Depressed mood Development Disease End Point Event FOXO1A gene Finasteride Gene Expression Genes Genetic Transcription Goals Human Hypoxia Incidence Induction of Apoptosis Intervention Intervention Studies Intervention Trial Laboratories Malignant neoplasm of prostate Mediating Medical Molecular Neoplasms Numbers Oxidation-Reduction Oxidoreductase Pathway interactions Patients Personal Satisfaction Phase Play Process Proliferating Prostate Prostate Cancer Prevention Trial Prostatectomy Prostatic Intraepithelial Neoplasias Proteins Public Health Randomized Receptor Activation Receptor Signaling Reporting Research Research Design Role Selenium Signal Pathway Signal Transduction Staging Stanolone Supplementation Testing Testosterone Tissue Sample Work Xenograft Model base bench to bedside cancer cell cancer diagnosis cancer risk cost men novel peroxiredoxin I pressure prevent programs prostate cancer prevention receptor expression restoration transcription factor

项目摘要

The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancer prevention. The approach is based on suppressing androgen signal transduction at two different steps simultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduce androgen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consists of three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperatively to modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Special emphasis is placed on the functional analysis of key targets and pathways responsible for the induction of apoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in a colony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxia produces a variety of molecular changes as a selective pressure for survival. There is recent evidence suggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. The above process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 is preferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is to investigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 in modifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical to the interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verify the effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostate tissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determine whether a high level of Prx1 diminishes the sensitivity to finasteride/selenium intervention. Every year, approximately 230,000 new cases of prostate cancer are diagnosed in the US, and some 30,000 men will die of this disease. As a public health problem, prostate cancer engenders huge medical care and human suffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly being recognized as an important aspect of prostate cancer control. Our goal is to find a way of managing the disease at an early stage in order to prevent it from becoming clinical relevant.

该计划项目的目标是开发一种新的机制驱动的前列腺癌策略预防。该方法基于在两个不同步骤抑制雄激素信号转导同时通过使用非那雄胺抑制二氢睾酮和硒的形成来减少雄激素受体（AR）表达。该计划是按照从实验室到临床的范例构建的，包括三个高度集成的项目。项目 1 是描述非那雄胺和硒如何协同作用调节某些分子事件来控制前列腺癌细胞的克隆扩张。特别的重点放在负责诱导的关键目标和途径的功能分析上非那雄胺/硒治疗后细胞凋亡。微环境缺氧常见于由于脉管系统异常而增殖的癌细胞集落。众所周知，缺氧产生各种分子变化作为生存的选择压力。最近有证据表明缺氧促进 AR 激活和雄激素反应基因的转录。这上述过程是由称为过氧化还原蛋白-1 (peroxiredoxin-1) 或 Prx1 的氧化还原调节蛋白介导的。 Prx1 是在前列腺上皮内瘤变和前列腺癌细胞中优先升高。项目2是为了研究缺氧/Prxl 刺激 AR 信号传导的机制并评估 Prx1 在改变非那雄胺/硒的癌症控制功效。项目 1 和 2 的结果对于对项目3临床试验结果的解读。拟进行短期干预试验来验证非那雄胺/硒对前列腺雄激素靶基因表达及细胞凋亡诱导的影响从前列腺切除术前患者获得的组织样本。试验的第二个目标是确定高水平的 Prx1 是否会降低对非那雄胺/硒干预的敏感性。每年，美国大约有 230,000 例前列腺癌新病例被诊断出来，大约 30,000 名男性将死于这种疾病。作为一个公共健康问题，前列腺癌带来了巨大的医疗保健和人类负担痛苦的代价。阻止小体积、低级别肿瘤的进展越来越受到重视被认为是前列腺癌控制的一个重要方面。我们的目标是找到一种管理方法疾病的早期阶段，以防止其成为临床相关的。