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）是美国和全世界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与暴露于烟草致癌物显著相关。在烟草致癌物暴露领域，特别是口腔和喉部，既往吸烟者和活跃吸烟者患浸润性癌症的风险仍然很高。这些癌症通常开始为口腔内的小的、通常不被注意的病变，并且超过三分之一的未经治疗的癌前口腔病变经历恶性转化为鳞状细胞癌。尽管传统的外科手术、放疗和化疗取得了进展，但SCCHN的总生存率在过去几十年中没有显著提高。此外，这些癌前病变的大部分复发，尽管完全手术切除。在侵袭性癌症发展之前可以实施的有效预防方法在降低SCCHN和其他烟草致癌物相关恶性肿瘤的发病率方面是非常期望的。目前的建议是专为预防癌前病变的头部和颈部使用组合的方法。在80-90%的SCCHN、SCCHN患者的异型增生病变和组织学正常粘膜中发现了表皮生长因子受体（EGFR）的过表达，表明EGFR上调代表癌发生的早期事件，并可作为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出适度的应答率。厄洛替尼与其他化学预防剂的组合可能通过协同生长抑制特性提高功效。然而，关键的挑战是找到一种可以提供协同效应的有效组合 生长抑制我们假设，使用厄洛替尼（EGFR抑制剂）与EGCG（多靶向天然化合物）的组合可能会降低癌症发病率，并使癌症高危患者受益。具体目标1侧重于这两种化合物之间的协同作用机制，特别强调FOXO-p21/p27/Bim和mTOR-pS 6信号传导及其通过AKT和ERK的调节。具体目标2试图确定活检组织样品中所选生物标志物的表达水平是否通过组合治疗有利地调节。

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.