Growth Factors and Lethal Prostate Cancer Signature

生长因子和致命的前列腺癌特征

• 批准号: 8063879
• 负责人: Meir Stampfer
• 金额: $ 53.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063879
• 关键词: Acids; Address; Apoptosis; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Biopsy Specimen; Blood specimen; C-Peptide; Cancer Etiology; Cancer Prognosis; Cause of Death; Cell Proliferation; Cessation of life; Clinical; Cohort Studies; DNA; Data; Databases; Development; Diagnosis; Disease; Ensure; Epidemiology; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Growth Factor; Haplotypes; Health; Health Professional; IGF1 gene; IGF2 gene; IGF2R gene; IGFBP1 gene; IGFBP3 gene; IRS2 gene; Immunohistochemistry; Indolent; Institutes; Insulin; Insulin Receptor; Joints; Left; Link; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metastatic Neoplasm to the Bone; Molecular; Molecular Biology; Molecular Profiling; Neoplasm Metastasis; PSA level; PSA screening; PTEN gene; Pathology; Pathway interactions; Pattern; Physicians; Plasma; Prevention strategy; Prostatic Neoplasms; Publications; Recurrence; Research; Research Infrastructure; Research Personnel; Resources; Risk; Role; SSTR1 gene; SSTR5 gene; Sampling; Serological; Somatomedins; Somatotropin; Stimulus; System; TMPRSS2 gene; Technology; Testing; Tissue Microarray; Tissues; Translating; Tumor Markers; Tumor Tissue; Universities; Up-Regulation; Variant; Work; aggressive therapy; angiogenesis; base; biobank; cancer risk; clinical practice; clinically relevant; cohort; cost; density; design; follow-up; genetic variant; human IGFBP2 protein; innovative technologies; insulin receptor substrate 1 protein; insulin signaling; insulin-related factor; men; mortality; multidisciplinary; novel; prospective; protein expression; public health relevance; receptor; repository; success; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): A central issue in prostate cancer (PCa) is to recognize potentially lethal cancer at diagnosis, and to identify the causes and underlying mechanisms that distinguish lethal from indolent disease. Using a case-only design, we will develop a molecular signature for potentially lethal PCa by comparing the RNA expression profiles of tumor tissue from subsequently lethal PCa cases to tumor tissue from men without known lethal disease. Collaborating with researchers at the Broad Institute of Harvard University/MIT, we propose to apply a novel but proven high-throughput profiling technology to assess RNA expression in archival tumor tissue using a 24,000 gene platform. Our previous work provided converging evidence of a key role of the insulin-like growth factor (IGF) system in PCa risk and progression. We have already assembled an extensive prospective clinical and serological database on PCa with up to 26 years of follow-up. Germline polymorphisms and plasma levels of the IGF axis have been assayed in many cases who provided a prediagnostic blood sample. We now propose to extend this work with additional IGF/insulin components, including germline variations and tumor expression, in relation to PCa progression and mortality. Using a case-only design, we will assess circulating biomarkers and tagging germline polymorphisms in the IGF/insulin axis, comparing lethal cases to men without known lethal disease. We will also assess alterations of IGF/insulin signaling in PCa tissue (RNA and protein expression) in relation to fatal PCa, and will integrate plasma and genetic biomarkers with tumor tissue data to illuminate gene pathways that are dysregulated. Based on intriguing preliminary data, we will characterize tumor samples for presence of the common gene translocation, the TMPRSS2:ERG fusion, and address whether fusion positive tumors are more likely to progress when exposed to high levels of IGF/insulin signaling. The research will be conducted in the Physicians' Health Study (PHS) and Health Professionals Follow-up Study (HPFS) cohorts among incident PCa cases diagnosed from 1982-2008. We have assembled a PCa tumor repository of 1,600 cases (178 fatal) for tissue marker assays and are constructing high-density tissue microarrays for quantitative immunohistochemistry and FISH assays. We will have levels of circulating biomarkers measured in plasma (N=1,881) and SNPs assayed on extracted DNA (N=2,281). All men with PCa are followed intensively for information on treatment, PSA rise, metastases and cause of death with complete follow-up through 2012. The RNA expression data will greatly enhance our understanding of the influence of the IGF/insulin dependent and independent pathways on development of lethal PCa, which will aid in designing targeted therapy and prevention strategies. Most studies of PCa progression are based on elevations of PSA levels. A major strength of our proposal is that we use the most clinically relevant endpoint, lethal PCa. From the molecular signature of lethal PCa, we can identify a small number of highly predictive markers that could be ultimately assessed in biopsy samples. Thus, the findings can be translated to clinical practice, enabling clinicians to identify with confidence which tumors require aggressive therapy. Use of this rich resource of existing data and infrastructure permits a highly cost-efficient study, and the cross-disciplinary team of collaborators with a longstanding record of working together will ensure success of this project. PUBLIC HEALTH RELEVANCE: Prostate cancer is among the most common cancers in men, and a major cause of cancer death. A central problem is that with PSA screening, many men are diagnosed with a cancer that would not cause them harm, and they undergo therapy unnecessarily. We propose to use an exciting innovative technology to identify a molecular tumor signature to distinguish prostate cancers that are indolent, and can safely be left untreated, from those that are potentially lethal and require aggressive therapy. We also plan to extend our work to identify the causes of lethal prostate cancer as they relate to the growth factor pathway.

描述（由申请人提供）：前列腺癌（PCA）的一个核心问题是识别诊断时潜在的致命癌症，并确定将致命疾病与懒惰疾病区分开的原因和潜在机制。使用仅病例设计的设计，我们将通过比较肿瘤组织的RNA表达谱，从后来致命的PCA病例到没有已知致命疾病的男性的肿瘤组织，从而开发出一种潜在致命PCA的分子特征。我们与哈佛大学/麻省理工学院Broad Institute的研究人员合作，我们建议采用一种新颖但经过证实的高通量分析技术，以使用24,000个基因平台评估档案肿瘤组织中的RNA表达。我们以前的工作为PCA风险和进展中的胰岛素样生长因子（IGF）系统的关键作用提供了融合的证据。我们已经在PCA上组装了广泛的前瞻性临床和血清学数据库，最多可进行26年的随访。在许多情况下，已经对IGF轴的种系多态性和血浆水平进行了测定。现在，我们建议使用其他IGF/胰岛素成分（包括生殖线变异和肿瘤表达）扩展这项工作，这些作品与PCA进展和死亡率有关。使用仅病例设计，我们将评估IGF/胰岛素轴中的循环生物标志物并标记种系多态性，将致命病例与没有已知致命疾病的男性进行比较。我们还将评估与致命PCA有关的PCA组织（RNA和蛋白质表达）中IGF/胰岛素信号传导的变化，并将血浆和遗传生物标志物与肿瘤组织数据相结合，以照亮失调的基因途径。基于有趣的初步数据，我们将表征肿瘤样本，存在公共基因易位，TMPRSS2：ERG融合，并解决融合阳性肿瘤在暴露于高水平的IGF/胰岛素信号传导时是否更有可能进展。该研究将在1982 - 2008年诊断出的PCA病例中，医师健康研究（PHS）和卫生专业人员随访研究（HPFS）同类进行。我们已经组装了一个用于组织标记分析的1,600例（178个致命）的PCA肿瘤存储库，并正在构建高密度组织微阵列，以进行定量的免疫组织化学和鱼类测定。我们将具有在血浆中测量的循环生物标志物（n = 1,881），并在提取的DNA上测定的SNP（n = 2,281）。所有患有PCA的男性都遵循有关治疗，PSA升高，转移和死亡原因的信息，直到2012年进行全面随访。RNA表达数据将极大地增强我们对IGF/胰岛素依赖性依赖性PCA和独立途径对致命PCA发展的影响的理解，这将有助于设计目标治疗和预防策略。大多数PCA进展的研究都是基于PSA水平的升高。我们建议的主要优势是我们使用最临床相关的终点，致命的PCA。从致命PCA的分子特征中，我们可以确定少数高度预测的标记，这些标记最终可以在活检样品中评估。因此，这些发现可以转化为临床实践，使临床医生能够确定哪些肿瘤需要积极的治疗。使用这种丰富的现有数据和基础架构资源可以进行一项高度成本效益的研究，并且合作者的跨学科团队具有长期的合作记录，将确保该项目的成功。 公共卫生相关性：前列腺癌是男性最常见的癌症之一，也是癌症死亡的主要原因。一个核心问题是，通过PSA筛查，许多男性被诊断出患有不会造成伤害的癌症，并且他们不必要地接受治疗。我们建议使用激动人心的创新技术来识别分子肿瘤特征，以区分懒惰的前列腺癌，并且可以安全地将未经治疗的癌症与潜在的致命疗法相比，不受治疗。我们还计划扩展我们的工作，以确定与生长因子途径相关的致命前列腺癌的原因。