癌细胞外环境对进展期口腔癌的分子靶向药物敏感性的影响研究

近年针对癌细胞表皮上皮生长因子受体（EGFR）的分子靶向药物Cetuximab对头颈部进展期癌的治疗取得了一定效果，但其特定适用人群等投用基准尚未确定，敏感性尚需提高。已发现口咽癌尤其口腔癌对该药相对敏感，但机制尚未阐明。本课题通过检测临床进展期口腔癌的细胞外环境变化诸如活性氧（ROS）升高、人乳头瘤病毒（HPV）感染以及癌细胞上EGFR等其他受体酪氨酸激酶（RTKs）的活性化情况，来明确癌细胞外环境的变化与RTKs的激活是否存在因果关系；通过细胞和动物实验，进一步观察癌细胞外环境变化与RTKs信号传导及抑制的具体途径，遵循是否有ROS升高、是否有HPV感染、是否有EGFR等RTKs激活的条件，来投用临床常用的分子靶向药物及针对可能新靶点的其他药物，检测癌信号传导的抑制效果及细胞凋亡情况，筛选出有效的投用基准，大幅提高分子靶向药物的敏感性，从而提高进展期口腔癌的生存率。

Cetuximab, an IgG1 monoclonal antibody against the ligand binding domain of EGFR， improves overall survival of patients with advanced head and neck cancer when combined with radiotherapy or platinum-based chemotherapy. However, the determinants of efficacy and sensitivity of EGFR-targeted therapy in advanced head and neck cancer have not been well defined. Oropharynx cancer, and especially oral cavity cancer were reported to be more sensitive to cetuximab as compared with other head and neck cancers, but what causes this sensitivity difference? The molecular mechanisms behind these findings are poorly understood. Firstly, in the present study we plan to determine reactive oxidative speaces(ROS) production in the tumoral extracellular environment, HPV infection, activations of EGFR and other receptor tyrosine kinases(RTKs) in patients with advanced oral cancer. Additionally, whether ROS production changes in the tumoral extracellular environment and HPV infection contribute to activations of RTKs in these patients will be also investigated. Thirdly, the pathway and signal of RTKs influenced by changes of the tumoral extracellular environment and HPV infection will be studied in cell line experiments and animal experiments. Fourthly, according to whether or not there is high increased ROS in tumoral extracellular environment, HPV infection or activations of RTKs, we will choose to use RTKs-targeted drug applied in clinical practice or newly found in our study, we will test their efficacy and sensitivity by evaluating RTKs inhibition and apoptosis in both cell line and animal experiments. Based on the above findings, we finally seek to screen for biomarkers associated with good response to RTKs-targeted therapy and then to greatly improve overall survival of advanced oral cancer.