Defining Clinical Response Genes in High-Risk Epithelial Ovarian Carcinoma

泰素和卡铂是治疗卵巢癌的主要临床重要药物，但大多数患者最终会对这些药物产生耐药性。耐药性发展的分子机制可能涉及化疗期间获得的肿瘤遗传特性以及导致耐药性的肿瘤固有遗传特性。可能有助于确定耐药性机制的研究类型包括细胞系体外研究和人类样本转录谱研究。我们已经开发了广泛的初步体外数据与紫杉醇耐药的转录。其他细胞系数据已经确定了范可尼贫血（FA）/BRCA中的基因 因此，在Fanconi-贫血患者的细胞的顺铂超敏性的观察中，发现它们的甲基化可能与铂抗性相关。该项目旨在建立在研究人员解决获得性耐药机制的初步工作基础上，并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PCR比较原发性和复发性成对肿瘤或免疫组织化学在存档的成对原发性和复发性肿瘤标本中评价与细胞系中紫杉醇耐药相关的约50种转录物的精确列表的表达。第二，通过对生殖系、原发性卵巢肿瘤和复发性肿瘤DNA中FA基因和途径的甲基化和功能研究，评估FA/BRCA基因家族在初始铂类敏感性和发展铂类耐药中的作用。第三，评估来自原发性卵巢癌肿瘤标本的显微解剖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与完成治疗后六个月内复发的妇女。该项目旨在鉴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，最终目标是为未来的药物开发确定潜在的治疗靶点。

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.