Novel targets to treat head and neck cancer in Veterans

 描述(由申请人提供)： 由于烟酒致癌物质的暴露，退伍军人患有头颈部鳞状细胞癌(SCCHN)的比例不成比例。尽管进行了积极的治疗，但SCCHN是一种毁灭性的疾病，预示着总体5年存活率只有50%左右。对SCCHN的全面基因组分析显示，其中约30%的肿瘤过度表达编码钙激活氯离子通道(TMEM16A/ANO1)的基因。机制研究表明，TMEM16A通过激活EGFR-ERK1/2途径促进肿瘤细胞生长。EGFR是FDA批准的唯一治疗SCCHN的分子靶点，然而预测抗EGFR治疗反应的关键治疗生物标志物(S)仍不清楚。在这里，我们建议研究TMEM16A和EGFR如何相互作用促进肿瘤的生长和进展。我们建议进行以下研究：1)确定通过TMEM16A的氯通量是否必要且足以激活EGFR信号；2)检测TMEM16A如何与EGFR相互作用，以及这种相互作用是否对于肿瘤细胞生长是必要的；以及3)使用患者样本和来自小鼠致癌模型的组织来确定TMEM16A表达/TMEM16A-EGFR相互作用是否对于口腔异型增生的发展以及最终发展为浸润性癌是必需的。在该项目结束时，我们打算将TMEM16A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.