Novel targets to treat head and neck cancer in Veterans

治疗退伍军人头颈癌的新靶点

• 批准号: 9138391
• 负责人: UMAMAHESWAR DUVVURI
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138391
• 关键词: 11q13; Address; Alcohols; Biology; Calcium; Carcinogen exposure; Carcinogens; Carcinoma; Cell Survival; Cetuximab; Chloride Channels; Chlorides; Chromosomal Duplication; Data; Development; Disease; Dysplasia; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; FDA approved; Genes; Genomics; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heavy Drinking; Larynx; MAPK3 gene; MEKs; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Oral cavity; Oxides; Pathway interactions; Patients; Phosphorylation; Premalignant; Prognostic Marker; Ras/Raf; Receptor Activation; Receptor Signaling; Regulation; Role; Sampling; Services; Signal Pathway; Signal Transduction; Therapeutic; Tissues; Tobacco use; Veterans; Work; aggressive therapy; cancer diagnosis; carcinogenesis; carcinogenicity; cell growth; chemical carcinogenesis; clinical investigation; experimental study; inhibitor/antagonist; molecular targeted therapies; mouse model; mutant; neoplastic cell; novel; novel anticancer drug; oral dysplasia; outcome forecast; overexpression; predicting response; public health relevance; receptor expression; response; small molecule inhibitor; targeted agent; therapeutic biomarker; therapeutic target; tobacco exposure; tool; tumor; tumor growth; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Veterans suffer at a disproportional rate from squamous cell carcinoma of the head and neck (SCCHN) due to carcinogen exposure from tobacco and alcohol. Despite aggressive treatments, SCCHN is a devastating disease that portends an overall 5-year survival of only ~50%. A comprehensive genomic analysis of SCCHN revealed that ~30% of these tumors overexpress a gene that encodes a calcium-activated chloride channel (TMEM16A/ ANO1). Mechanistic studies have shown that TMEM16A contributes to tumor cell growth by activating the EGFR-ERK1/2 pathway. EGFR is the only FDA-approved molecular therapeutic target in SCCHN, yet the critical therapeutic biomarker(s) that predict response to anti-EGFR therapy remains unknown. Here, we propose to investigate the how TMEM16A and EGFR interact with each other to promote tumor growth and progression. We propose the following studies: 1) determine whether chloride flux through TMEM16A is necessary and sufficient to activate EGFR signaling; 2) examine how TMEM16A interacts with EGFR, and if this interaction is necessary for tumor cell growth; and 3) use a patient samples and tissues derived from a mouse model of carcinogenesis to determine if TMEM16A expression / TMEM16A-EGFR interaction is required for the development of oral dysplasia and ultimately progression to invasive carcinoma. At the conclusion of this project, we intend to implicate TMEM16A as a direct therapeutic target for the treatment of Veterans with OSCC.

 描述（由申请人提供）： 由于暴露于烟草和酒精的致癌物质，退伍军人患头颈部鳞状细胞癌（SCCHN）的比例不成比例。尽管有积极的治疗，SCCHN是一种毁灭性的疾病，预示着总体5年生存率仅为~ 50%。对SCCHN的全面基因组分析显示，约30%的这些肿瘤过度表达编码钙激活氯离子通道（TMEM 16 A/ANO 1）的基因。机制研究表明，TMEM 16 A通过激活EGFR-ERK 1/2途径促进肿瘤细胞生长。EGFR是SCCHN中唯一FDA批准的分子治疗靶点，但预测抗EGFR治疗反应的关键治疗生物标志物仍未知。在这里，我们打算研究TMEM 16 A和EGFR如何相互作用以促进肿瘤的生长和进展。我们提出了以下研究：1）确定通过TMEM 16 A的氯通量是否是激活EGFR信号传导所必需的和足够的; 2）检查TMEM 16 A如何与EGFR相互作用，以及这种相互作用是否是肿瘤细胞生长所必需的;和3）使用患者样品和来源于癌发生小鼠模型的组织来确定TMEM 16 A表达/TMEM 16 A-EGFR相互作用是口腔发育不良发展并最终进展为浸润性癌所必需的。在本项目结束时，我们打算将TMEM 16 A作为治疗退伍军人口腔鳞癌的直接治疗靶点。