MOLECULAR CLASSIFICATION OF PROSTATE CANCER

前列腺癌的分子分类

• 批准号: 6074267
• 负责人: WILLIAM L GERALD
• 金额: $ 45万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6074267
• 关键词: androgens; carcinoma; clinical research; cooperative study; gene expression; genetic techniques; histopathology; human subject; male; molecular genetics; neoplasm /cancer classification /staging; neoplasm /cancer genetics; prostate neoplasms

Prostate cancer is the most commonly diagnosed cancer in men and affects millions of people. In recent years both the detection and incidence have increased dramatically. The natural history of prostate cancer is enigmatic leading to significant controversies concerning screening tests and proper therapeutic management. The only established systemic therapy for this disease focuses on androgen ablation. Androgen deprivation induces programmed cell death in hormone-dependent prostatic cancer. However, androgen-independent cells are present early in the evolution of prostate cancer and virtually all patients eventually develop androgen-independent tumor, a serious clinical problem for which no effective therapy exists. The mechanisms of development and biochemical pathways that contribute to androgen-independent growth are unknown. Existing classifications of prostate cancer offer little information regarding prognosis or predicted response to therapy for individual patients. Molecular profiles that distinguish androgen-dependent from androgen-independent prostate cancer will provide insight into the critical pathways that regulate tumor growth and response to therapy, and can be used for classification with regard to hormone sensitivity. The overall goal of our research program is to characterize the molecular events underlying the clinical features of prostate cancer and provide a basis for molecular classification and targeted therapy. Comprehensive analyses of a human prostate cancer xenograft have demonstrated that expression levels in large numbers of genes change dramatically in the course of selection for androgen-independent growth. Androgen-independent tumors have a distinct molecular profile resulting from altered expression of many genes, some of which are known to play a role in the androgen signal transduction pathway, but many are of unknown function. Based on this encouraging result we expect that androgen-independent primary human prostate cancer will have a distinct molecular profile. We propose 1) to define molecular profiles that are representative of androgen-independent prostate carcinoma by comprehensive, microarray-based gene expression analysis and comparison of androgen-dependent and androgen independent tumors, 2) to develop robust molecular histopathologic methods to identify and quantitate androgen-dependent and -independent tumor cell subclones within primary human prostate carcinomas for molecular classification of individual tumors, and 3) to analyze the relationship between molecular classification and clinical course of disease in statistically sound retrospective and prospective studies. These studies will provide the basis for an in-depth understanding of the role of androgens in prostate cancer, mechanisms for development of hormone refractory disease and the clinical utility of a molecular classification based on this information.

前列腺癌是男性最常见的癌症，影响数百万。 近年来，检测和发病率都大大增加。 前列腺癌的自然历史是神秘的，导致有关筛查测试和适当治疗管理的重大争议。 该疾病的唯一已建立的全身疗法专注于雄激素消融。 雄激素剥夺诱导激素依赖性前列腺癌中编程的细胞死亡。 然而，雄激素独立的细胞存在于前列腺癌的进化早期，几乎所有患者最终都会发展为雄激素独立的肿瘤，这是一个严重的临床问题，不存在有效的治疗。 有助于雄激素独立生长的发育和生化途径的机制尚不清楚。 前列腺癌的现有分类几乎没有关于预后或对个别患者治疗的预测反应的信息。 将雄激素依赖性与雄激素独立的前列腺癌区分开的分子谱将提供对调节肿瘤生长和对治疗反应的关键途径的见解，并且可用于与激素敏感性有关。 我们研究计划的总体目标是表征前列腺癌临床特征的基础事件，并为分子分类和靶向治疗提供基础。对人前列腺癌异种移植的全面分析表明，在选择雄激素非依赖性生长的过程中，大量基因的表达水平发生了巨大变化。 雄激素非依赖性肿瘤具有明显的分子特征，这是由于许多基因的表达改变而产生的，其中一些基因在雄激素信号转导途径中起作用，但许多基因具有未知功能。 基于这种令人鼓舞的结果，我们预计与雄激素无关的原发性人前列腺癌将具有独特的分子特征。 We propose 1) to define molecular profiles that are representative of androgen-independent prostate carcinoma by comprehensive, microarray-based gene expression analysis and comparison of androgen-dependent and androgen independent tumors, 2) to develop robust molecular histopathologic methods to identify and quantitate androgen-dependent and -independent tumor cell subclones within primary human prostate carcinomas for molecular classification单个肿瘤和3）分析统计性回顾性和前瞻性研究中分子分类与疾病临床过程之间的关系。 这些研究将为深入了解雄激素在前列腺癌中的作用，激素难治性疾病的发展机制以及基于该信息的分子分类的临床实用性提供基础。