PPG PROJECT 3

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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得前列腺癌成为化学预防的主要候选者。前列腺癌的病因尚不完全清楚，但家族因素可能起着重要作用。最近的数据表明，遗传可能在20-25%的早发性前列腺癌中起作用。 大量研究表明，多胺调节在细胞增殖和癌变过程中起重要作用。最近的研究表明，多胺可能影响参与肿瘤侵袭的基因的表达，包括参与前列腺癌的基因。这些和其他的实验数据提供了一个理论基础的组织多胺含量的耗竭作为前列腺恶性肿瘤的化学预防的策略。 我们提出了一个以人群为基础的研究前列腺癌病因的项目，它将整合（a）遗传易感基因;（B）遗传改变;（3）流行病学风险因素，包括家族史和环境暴露。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，我们将检测该基因突变的样本。这样做是为了确定该基因在群体中的频率分布和突变率。流行病学风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影响。 本项目中要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，多胺合成途径上的关键酶）的不可逆抑制剂，是否可以抑制前列腺癌高遗传风险个体前列腺组织中的组织多胺含量和进展相关基因。主要终点是多胺、腐胺、亚精胺和精胺，这些是最佳细胞增殖所必需的。我们的团队在DFMO作为预防和治疗药物方面有着丰富的经验。本更新方案PPG项目II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堂兄弟男性中进行一项DFMO的随机安慰剂对照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堂兄弟，并且在进入研究时年龄在70岁以下且35岁或以上。受试者将不会有任何限制性的慢性疾病，将项目少于5年的生存或将排除前列腺活检。还将进行血清总PSA和游离PSA以及前列腺超声和体积测量。将对前列腺进行六等分穿刺活检，进行组织病理学评价，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和确定可能的遗传联系及其与环境暴露和据报告与前列腺癌有关的其他风险因素的相互作用。受试者将被随机分成相等大小的组，每天服用安慰剂或500 mg 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，并将其与对前列腺的生物学效应进行比较。 将分析临床试验和项目II的结果。最佳地，我们将能够确定抑制多胺含量和改变SEB而不产生临床副作用的剂量。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变异或易感基因的频率分布和频率，并研究前列腺癌易感基因或遗传变异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.