Molecular Studies Of Ovarian Cancer And The Wnt Pathway

卵巢癌和 Wnt 通路的分子研究

• 批准号: 6667925
• 负责人: Patrice J. Morin
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/6667925
• 关键词: cadherins; carcinogenesis; colon neoplasms; gene expression; gene mutation; human tissue; molecular genetics; molecular oncology; neoplasm /cancer genetics; oncogenes; oncoproteins; ovary neoplasms; serial analysis of gene expression; tumor suppressor genes; tumor suppressor proteins

These studies focus on two topics: ovarian cancer and the Wnt pathway in human cancers. Ovarian cancer is the fifth most common cancer and the fourth leading cause of cancer death among women in the United States. Because of a lack of powerful screening and diagnostic tests, early detection has been difficult. Moreover, the molecular mechanisms important in ovarian cancer initiation, progression and resistance to chemotherapeutic drugs remain largely unknown. We are using SAGE and other state-of-the-art molecular techniques to identify tumor markers and gain a greater understanding of the molecular pathways involved in ovarian tumorigenesis and cisplatin resistance. Indeed, the analysis of gene expression in ovarian cancer suggests the involvement many novel pathways in this disease. We are currently investigating the roles of the different pathways using molecular and cellular approaches. Our ultimate goal is the development of mechanism-based interventions for ovarian cancer patients. For example, we have recently found an important role for extracellular matrix (ECM) remodeling in the development of drug resistance in ovarian cancer. Inhibition of ECM-cancer cell interactions may therefore provide novel therapeutic opportunities for the development of strategies to circumvent the problem of drug resistance in ovarian cancer. The Wnt pathway, which was originally defined as a crucial pathway for body patterning during fruit fly development, has recently been implicated in human cancer. APC, a gene mutated in 80% of all colon cancers, is involved in the downregulation of the Wnt pathway. Moreover, colon tumors containing wild-type APC, frequently contain activating mutations in other members of the pathway emphasizing its importance for colon cancer progression. We are developing inducible systems that may be useful in the identification of downstream transcriptional targets as well as upstream regulatory components of the pathway.

这些研究侧重于两个主题：卵巢癌和人类癌症中的WNT途径。卵巢癌是美国女性第五大癌症，也是癌症死亡的第四个主要原因。由于缺乏强大的筛查和诊断测试，很难早期检测。此外，在卵巢癌的开始，进展和对化学治疗药物的抗性中重要的分子机制仍然很大程度上未知。我们正在使用SAGE和其他最先进的分子技术来鉴定肿瘤标记，并对参与卵巢肿瘤发生和顺铂耐药的分子途径有更深入的了解。实际上，对卵巢癌基因表达的分析表明，这种疾病的许多新途径参与。我们目前正在使用分子和细胞方法研究不同途径的作用。我们的最终目标是开发基于机制的卵巢癌患者的干预措施。例如，我们最近发现了细胞外基质（ECM）重塑在卵巢癌中耐药性发展中的重要作用。因此，抑制ECM-Canter细胞相互作用可能会为制定策略避免卵巢癌耐药性问题提供新的治疗机会。 Wnt途径最初被定义为在果蝇发育过程中的身体模式的关键途径，最近与人类癌症有关。 APC是所有结肠癌中80％突变的基因，参与WNT途径的下调。此外，含有野生型APC的结肠肿瘤经常包含该途径其他成员的激活突变，这强调了其对结肠癌进展的重要性。我们正在开发可诱导系统，这些系统可能可用于识别下游转录靶标以及该途径的上游调节组件。