TUMOR SUPPRESOR GENE PROMOTER HYPERMETHYLATION FOR DETECTION OF HEAD AND NECK

用于头颈部检测的肿瘤抑制基因启动子高甲基化

• 批准号: 7929609
• 负责人: DAVID SIDRANSKY
• 金额: $ 34.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929609
• 关键词: Candidate Disease Gene; Cell Line; Deoxycytidine; Detection; Drug resistance; Early Diagnosis; Epidermal Growth Factor Receptor; Genes; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Hypermethylation; In Vitro; Malignant Neoplasms; Pathway interactions; Patient Monitoring; Reproduction spores; Structure; Testing; Transfection; Tumor Suppressor Genes; base; chemotherapy; cohort; in vivo; mouse model; novel; promoter; prospective; tumor; tumor progression

We and others have demonstrated that silencing of tumor suppressor genes associated with promoter hypermethylation is a common feature of many human cancers. We have identified several novel tumor suppressor genes inactivated by promoter hypermethylation, as well as candidate genes for use in detection strategies. We propose continue to identify and characterize hypermethylated genes in squamous cell carcinoma of the head neck (HNSCC) and will identify novel promoter hypermethylated genes by: (1) A candidate gene approach based on testing genes found to be hypermethylated in other tumors or on the functional structure and biologic plausibility of the candidate gene and (2) A functional screen looking for genes that are up-regulated following treatment with demethylating agents (5-Aza-deoxycytidine). Newly identified hypermethylated genes will be characterized for functional significance and biologic activity in tumor progression. We will apply a modified pharmacologic unmasking approach to define promoter hypermethylated genes whose inactivation contributes to drug resistance to conventional chemotherapeutic and pathway (EFGR) directed therapy. Candidate hypermethylated tumor suppressor genes will be validated in drug resistant cell lines by transfection of candidate genes in in vitro and in vivo mouse models. These genes will then be validated in prospective trials and retrospective cohorts treated with conventional chemotherapy and EGFR pathway specific agents. Novel promoter hypermethylatedtargets will be incorporated into a second SPORE proposal (project #2) for use as markers for the early detection and monitoring of patients with head and neck cancer.

我们和其他人已经证明了肿瘤抑制基因的沉默与启动子相关