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: 7516200
• 负责人: MICHAEL V. SEIDEN
• 金额: $ 32.8万
• 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/7516200
• 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重要临床药物，但大多数患者最终会对这些药物产生抗药性。耐药性形成的分子机制可能涉及化疗过程中获得的肿瘤的遗传特性以及导致耐药性的肿瘤的内在遗传特性。可能有助于确定耐药机制的研究类型包括对细胞系的体外研究和对人类标本的转录图谱研究。我们已经开发了大量与紫杉醇耐药相关的转录本的体外初步数据。其他细胞系数据已经确定了Fanconi贫血(FA)/BRCA的基因 通路及其甲基化可能与铂耐药有关，这源于对范可尼贫血患者细胞顺铂超敏反应的观察。该项目寻求在研究人员解决获得性耐药机制的初步工作的基础上，通过以下具体目标探索解决耐药内在机制的强大转录模型。首先，使用定量聚合酶链式反应比较原发和复发配对肿瘤或免疫组织化学方法评估与紫杉醇耐药相关的约50个转录本在细胞系中的表达。其次，通过对配对的生殖系、卵巢原发肿瘤和复发肿瘤DNA中FA基因和通路的甲基化和功能研究，评估FA/BRCA基因家族在初始铂敏感性和铂耐药形成中的作用。第三，评估从原发卵巢癌肿瘤标本中显微解剖的上皮细胞中的基因表达谱，以区分临床缓解至少一年的妇女和完成治疗后六个月内复发的妇女。该项目旨在确定与紫杉醇和卡铂耐药的内在或获得性机制相关的基因和/或途径，最终目标是确定未来药物开发的潜在治疗靶点。