Defining Clinical Response Genes in High-Risk Epithelial Ovarian Carcinoma

定义高危上皮性卵巢癌的临床反应基因

• 批准号: 7690256
• 负责人: MICHAEL V. SEIDEN
• 金额: $ 29.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7690256
• 关键词: Address; Archives; Carboplatin; Cell Line; Cells; Cisplatin; Clinical; DNA; Data; Development; Disease remission; Drug resistance; Epithelial; Epithelial Cells; Fanconi Anemia-BRCA Pathway; Fanconi' s Anemia; Future; Gene Expression; Gene Family; Genes; Genetic; Germ Lines; Goals; Human; Hypersensitivity; Immunohistochemistry; In Vitro; Link; Malignant neoplasm of ovary; Methylation; Modeling; Molecular; Molecular Profiling; Ovarian Carcinoma; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Polymerase Chain Reaction; Property; Recurrence; Recurrent tumor; Relapse; Research Design; Research Personnel; Resistance; Resistance development; Risk; Role; Specimen; Transcript; Woman; Work; chemotherapy; design; drug development; ovarian neoplasm; response; stem; therapeutic target; tumor

Taxol and Carboplatin are drugs of major clinical importance in the treatment of ovarian carcinoma; but the majority of patients will eventually develop resistance to these drugs. Molecular mechanisms in the development of drug resistance might involve genetic properties of tumors acquired during chemotherapy as well as intrinsic genetic properties of the tumors that contribute to resistance. The types of studies that may be useful for defining mechanism of drug resistance include in-vitro studies on cell lines and transcriptional profiling studies in human specimens. We have developed extensive preliminary in-vitro data on transcripts linked to Taxol resistance. Other cell line data have identified genes in the Fanconi Anemia (FA)/BRCA pathway and their methylation as being potentially related to platinum resistance stemming from observations of the cisplatin hypersensitivity of cells from Fanconi-anemia patients. This project seeks to build upon preliminary work by the investigators addressing acquired mechanisms of drug resistance as well as exploring robust transcriptional models addressing intrinsic mechanisms of drug resistance by the following specific aims. First, evaluate the expression of a refined list of about 50 transcripts linked to Taxol resistance in cell lines using either quantitative PCR comparing primary and recurrent paired tumors or immunohistochemistry in archived paired primary and recurrent tumor specimens. Second, evaluate the role of FA/BRCA gene family in initial platinum sensitivity and evolving platinum resistance by methylation and functional studies of FA genes and pathway in matched sets of germ line, primary ovarian tumor, and recurrent tumor DNA. Third, evaluate gene expression profiles in micro-dissected epithelial cells from primary ovarian cancer tumor specimens that distinguish women who had clinical remission for at least one year versus those who relapsed within six months of completing therapy. This project is designed to identify genes and/or pathways that are associated with intrinsic or acquired mechanisms of Taxol and Carboplatin resistance with the ultimate goal of identifying potential therapeutic targets for future drug development.

紫杉醇和卡铂是治疗卵巢癌的主要临床重要性的药物。但是大多数患者最终将对这些药物产生抗药性。耐药性发育中的分子机制可能涉及化学疗法期间获得的肿瘤的遗传特性以及肿瘤的内在遗传特性，这些肿瘤有助于耐药。可能有助于定义耐药性机理的研究类型包括对人类标本中细胞系和转录分析研究的体外研究。我们已经开发了有关与紫杉醇耐药性相关的成绩单的广泛初步的视野内数据。其他细胞系数据已经鉴定出Fanconi贫血（FA）/BRCA中的基因 途径及其甲基化可能与铂抗血症患者的细胞超敏反应的观察到潜在的铂耐药性有关。该项目旨在基于研究人员的初步工作，该研究人员针对获得的耐药性机制，并探索稳健的转录模型，以解决以下特定目标来解决耐药性内在机制。首先，使用定量PCR评估与细胞系中与紫杉醇抗性相关的大约50种转录本的表达，以比较原发性和复发的成对肿瘤或免疫组织化学在存档的成对的原发性和复发性肿瘤标本中。其次，评估FA/BRCA基因家族在初始铂敏感性中的作用，并通过甲基化和FA基因和途径的功能研究在匹配的生殖系，原发性卵巢肿瘤和复发性肿瘤DNA中的功能研究。第三，评估来自原发性卵巢癌肿瘤标本的微滴上皮细胞中的基因表达谱，这些标本与在完成治疗后六个月内复发至少一年的女性区分了临床缓解至少一年的女性。该项目旨在识别与紫杉醇和卡铂耐药机制相关的基因和/或途径，其最终目标是确定未来药物开发的潜在治疗靶标。