Mechanism of chemopreventive synergism from the combination of EGCG and Erlotinib

描述(申请人提供)：头颈部鳞状细胞癌(SCCHN)是美国和世界范围内的一个严重的医疗保健问题，是所有癌症中最致命的之一，在美国每年有超过48,000个新诊断病例和15,000人死亡。SCCHN与烟草致癌物的接触密切相关。在烟草致癌物暴露的领域--特别是口腔和喉部--吸烟者和活跃吸烟者患浸润性癌症的风险仍然很高。这些癌症通常始于口腔内的小病变，通常不被注意到，超过三分之一的未经治疗的癌前口腔病变会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，但在过去的几十年里，SCCHN的总体存活率并没有显著提高。此外，尽管完全手术切除，这些癌前病变中的很大一部分仍会复发。为了减少SCCHN和其他烟草致癌物相关恶性肿瘤的发病率，在浸润性癌症发生之前就实施有效的预防方法是非常必要的。目前的建议是为使用组合方法预防头颈部癌前病变而设计的。表皮生长因子受体(EGFR)在80-90%的SCCHN、异常增生性皮损和组织学正常的SCCHN中均有过表达，提示EGFR上调是SCCHN发生的早期事件，可作为预防策略干预的重要靶点。然而，作为单一药物，EGFR抑制剂仅显示出适度的应答率。厄洛替尼与其他化学预防药物联合使用可能会通过协同抑制生长而提高疗效。然而，关键的挑战是找出一种能够提供协同效应的有效组合 生长抑制。我们推测，将EGFR抑制剂厄洛替尼与EGCG(一种多靶点天然化合物)联合使用，可能会降低癌症发病率，并极大地有利于癌症高危患者。具体目的1重点阐述这两种化合物协同作用的机制，特别是FOXO-p21/p27/Bim和mTOR-pS6信号转导以及AKT和ERK对它们的调控。具体目标2试图确定活组织样本中选定的生物标记物的表达水平是否受到联合治疗的有利调节。

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.