PPG PROJECT 3

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。前列腺癌是美国最常见的癌症，约占男性癌症发病率的30%和癌症死亡率的12%。前列腺癌的高患病率和癌症起始事件与侵袭性疾病发展之间的长潜伏期使其成为化学预防的首选。前列腺癌的病因尚不完全清楚，但家族因素可能起重要作用。最近的数据表明，遗传可能在20-25%的早期前列腺癌发病中起作用。广泛的研究表明，多胺调节在细胞增殖和癌变中起重要作用。最近的研究表明，多胺可能影响肿瘤侵袭相关基因的表达，包括前列腺癌相关基因。这些和其他实验数据为组织多胺含量的消耗作为化学预防前列腺恶性肿瘤的策略提供了基本原理。我们提出一个以人群为基础的项目来研究前列腺癌的病因，该项目将整合(a)遗传易感基因(s)；(b)基因改变；(3)家族史、环境暴露等流行病学危险因素。如果在本研究过程中克隆了一个主要的前列腺癌易感基因，我们将测试该基因的突变样本。这样做是为了确定该基因在人群中的频率分布和外显率。流行病学危险因素信息将用于确定易感基因的表达或其他遗传改变是否可能受到环境因素的改变。本项目拟检验的主要假设是确定α -二氟甲基鸟氨酸（DFMO），一种酶激活的鸟氨酸脱羧酶（OCD，多胺合成途径的关键酶）的不可逆抑制剂，是否能抑制前列腺癌高遗传风险个体前列腺组织中多胺含量和进展相关基因。主要终点将是多胺、腐胺、亚精胺和精胺，它们是最佳细胞增殖所必需的。我们的团队在使用DFMO作为预防和治疗药物方面有着丰富的经验。PPG项目II更新协议的具体目标是：1。在有早发性前列腺癌家族史的先证者的兄弟和表兄男性中进行一项随机安慰剂对照IIb期试验。先证者年龄在70岁以下。临床试验的参与者将是先证者的兄弟或男性一级表兄妹，在研究开始时年龄在70岁以下和35岁以上。参与者不得有任何限制性慢性疾病，预计生存期少于5年或无法进行前列腺活检。血清总PSA和游离PSA以及前列腺超声和体积测量也将完成。将对前列腺进行六分仪穿刺活检，进行组织病理学评估，并测量多胺含量和替代中间生物标志物（seb）（项目II）。该项目还将试图寻找并确定可能的遗传联系及其与环境暴露和其他与前列腺癌相关的风险因素的相互作用。参与者将被随机分为等量组，分别服用安慰剂或每天500毫克DFMO，并仔细监测副作用，包括听力学变化。一年后，将再次进行六分仪活检，并测量实验室参数，如上所述。2. 仔细评估DFMO在该人群中的副作用，并将其与前列腺的生物学效应进行比较。将分析临床试验和二期项目的结果。理想情况下，我们将能够确定在不产生临床副作用的情况下抑制多胺含量和改变SEB的剂量。我们已经成功地在结肠癌高危人群中实现了这一目标。此外，我们将确定人群中遗传改变或易感基因的频率分布和外显率，并调查前列腺癌易感基因或遗传改变与环境因素之间可能的相互作用及其与癌症风险的关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer is the most common cancer diagnosed in the United States and accounts for about 30% of cancer incidence and 12% of cancer mortality among men. The high prevalence rate and the long latent period between the cancer-initiating events and the development of invasive disease makes prostate cancer a prime candidate for chemoprevention. The etiology of prostate cancer is incompletely understood, but familial factors probably play a significant role. Recent data suggest that heredity may play a role in 20-25% of early age onset prostate cancer. Extensive investigations have demonstrated that polyamine regulation is important in cellular proliferation and carcinogenesis. Recent studies indicate that polyamines may affect the expression of genes involved in tumor invasion, including genes involved in prostate cancer. These and other experimental data provide a rationale for depletion of tissue polyamine content as a strategy for chemoprevention of prostate malignancy. We propose a population-based project to study etiologic factors of prostate cancer which will integrate (a) inherited susceptibility gene(s); (b) genetic alterations; and (3) epidemiologic risk factors including family history and environmental exposures. In the event that a major prostate cancer susceptibility gene is cloned during the course of this study, we will test the sample for mutations in that gene. This will be done in order to determine the frequency distribution and penetrance of that gene in the population. Epidemiologic risk factor information will be used to determine whether the expression of susceptibility genes or other genetic alterations may be modified by environmental factors. The major hypothesis to be tested in this project is to determine whether alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (OCD, the key enzyme on the pathway to polyamine synthesis), can suppress tissue polyamine content and progression-related genes in prostate tissue of individuals at high genetic risk for prostate cancer. The primary endpoints will be the polyamines, putrescine, spermidine, and spermine which are essential for optimal cell proliferation. Our group has had extensive experience with DFMO as a prevention and therapeutic agent. The specific aims of this updated protocol Project II of PPG are: 1. To conduct a randomized placebo-controlled phase IIb trial of DFMO in brothers and first-cousin males of probands with a familial history of early age onset prostate cancer. Probands will be below age 70. Participants in the clinical trial will be brothers or male first degree cousins of the proband and below age 70 and 35 years or older at time of study entry. Participants will not have any limiting chronic disease that would project less than a 5-year survival or would preclude prostate biopsy. Serum total and free PSA as well as a prostate ultrasound with volume measurements will also be done. Sextant needle biopsies of the prostate gland will be performed, histopathologic evaluation made, and polyamine content and surrogate intermediate biomarkers (SEBs) measured (Project II). This project will also attempt to look for and to identify possible genetic links and their interactions with environmental exposures and other risk factors reported to be associated with prostate cancer. Participants will be randomized into equal-sized groups taking placebo or 500 mg per day of DFMO and carefully monitored for side effects, including audiologic changes. After one year, sextant biopsies will again be done and laboratory parameters measured, as above. 2. To carefully assess the side effects of DFMO in this population and to compare them to the biological effect on the prostate gland. Results from the clinical trial and from Project II will be analyzed. Optimally, we will be able to determine the dose at which polyamine content is suppressed and SEB changed without clinical side effects being produced. We have successfully accomplished such a goal in individuals at high risk for colon cancer. Additionally, we will determine the frequency distribution and penetrance of genetic alterations or susceptibility genes in the population and investigate possible interactions between prostate cancer susceptibility genes or genetic alterations and environmental factors and their relationship to cancer risk.