Novel targets to treat head and neck cancer in Veterans

 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。

 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.