Mechanism of chemopreventive synergism from the combination of EGCG and Erlotinib

描述（由申请人提供）：头颈部鳞状细胞癌（SCCHN）是美国和世界范围内严重的医疗保健问题，是所有癌症中最致命的癌症之一，在美国每年有超过48,000例新诊断病例和15,000例死亡。SCCHN与接触烟草致癌物显著相关。在接触烟草致癌物的部位，尤其是口腔和喉部，前吸烟者和活跃吸烟者都有很高的患浸润性癌症的风险。这些癌症通常始于口腔内的小病变，通常不被注意，超过三分之一未经治疗的癌前口腔病变会恶性转化为鳞状细胞癌。尽管在传统的外科手术、放疗和化疗方面取得了进展，但在过去的几十年里，SCCHN的总生存率并没有显著提高。此外，这些癌前病变的很大一部分，尽管完全手术切除复发。一种有效的预防方法可以在浸润性癌症发生之前实施，这对于减少SCCHN和其他烟草致癌物质相关恶性肿瘤的发病率是非常可取的。目前的建议是为了预防头和颈部的恶性病变使用组合的方法。表皮生长因子受体（EGFR）在80-90%的SCCHN、SCCHN患者的发育不良病变和组织学正常粘膜中均存在过表达，这表明EGFR上调代表了癌变的早期事件，可能是制定预防策略的重要干预目标。然而，EGFR抑制剂作为单一药物仅显示适度的反应率。厄洛替尼与其他化学预防药物联用可能通过协同生长抑制特性提高疗效。然而，关键的挑战是确定一种能够提供协同作用的有效组合

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the head and neck (SCCHN), a serious healthcare problem in the United States and worldwide, is one of the deadliest of all cancers with more than 48,000 new cases diagnosed and 15,000 deaths each year in the United States. SCCHN is significantly associated with exposure to tobacco carcinogens. Both former and active smokers remain at high risk of developing invasive cancer in tobacco carcinogen-exposed fields - especially the oral cavity and larynx. These cancers generally begin as small, often unnoticed, lesions inside the mouth and more than one third of untreated precancerous oral lesions undergo malignant transformation into squamous cell cancer. Despite advances in conventional surgical procedures, radiotherapy, and chemotherapy, the overall survival rate for SCCHN has not been significantly improved in past few decades. Moreover, a large fraction of these precancerous lesions recur despite complete surgical removal. An effective prevention method which can be implemented before invasive cancer develops is highly desirable in reducing the incidence of SCCHN and other tobacco carcinogen-related malignancies. The current proposal is designed for the prevention of premalignant lesions of the head and neck using a combinatorial approach. The overexpression of epidermal growth factor receptor (EGFR) has been found in 80-90% of SCCHN, in dysplastic lesions and histologically normal mucosa from SCCHN patients, indicating that EGFR upregulation represents an early event in carcinogenesis and may serve as an important target for intervention in developing preventive strategies. However, EGFR inhibitors showed only modest response rates as single agents. The combination of erlotinib with other chemopreventive agents might improve efficacy through synergistic growth inhibitory properties. However, the critical challenge is to identify an effective combination which can offer synergistic growth inhibition. We hypothesize that using the combination of erlotinib, an EGFR inhibitor, with EGCG, a multi targeted natural compound, may reduce cancer incidence and greatly benefit patients at high risk for developing cancer. Specific Aim 1 focuses on the mechanism of synergy between these two compounds with special emphasis on FOXO-p21/p27/Bim and mTOR-pS6 signaling and their regulation by AKT and ERK. Specific Aim 2 seeks to determine whether the expression levels of selected biomarkers in biopsied tissue samples are favorably modulated by the combined treatment.