Mechanism of chemopreventive synergism from the combination of EGCG and Erlotinib

EGCG与厄洛替尼联用的化学预防协同作用机制

• 批准号: 8244871
• 负责人: A.R.M. Ruhul Amin
• 金额: $ 7.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244871
• 关键词: Aftercare; Apoptosis; Apoptotic; Biological Markers; Biopsy; Cancer Cell Growth; Cancer cell line; Cell Cycle Arrest; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Combined Modality Therapy; Cytostatics; Data; Development; Diagnosis; Disease; EGFR Protein Overexpression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigallocatechin Gallate; Erlotinib; Event; Excision; Exposure to; FDA approved; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Healthcare; Histologic; In Vitro; Incidence; Intervention; Larynx; Lesion; Link; MAP2K1 gene; Malignant - descriptor; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Methods; Molecular Target; Mucous Membrane; Mutation; Operative Surgical Procedures; Oral cavity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Play; Premalignant; Prevention; Prevention strategy; Property; Proteins; Proto-Oncogene Proteins c-akt; Radiation therapy; Recurrence; Regulation; Ribosomal Proteins; Role; Sampling; Signal Transduction; Smoker; Survival Rate; Testing; Tissue Sample; Tissues; Tobacco-Associated Carcinogen; Translations; United States; Up-Regulation; Xenograft procedure; base; carcinogenesis; chemotherapy; combinatorial; design; gallocatechol; high risk; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; novel strategies; oral lesion; receptor upregulation; response; synergism

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. PUBLIC HEALTH RELEVANCE: Both active and former smokers remain at high risk of developing invasive cancer in tobacco carcinogen- exposed fields - especially the oral cavity and larynx and a chemopreventive approach is highly desirable to reduce the number of tobacco carcinogen-related malignancies including head and neck. This project focuses on the identification of molecular targets which are critical for the synergistic chemopreventive potentia of a combination of EGFR TKI erlotinib and green tea polyphenol EGCG. This combined chemoprevention treatment is a novel approach to blocking carcinogenesis and may further impact and reduce cancer incidence and help to design Phase II trial.

描述（由申请人提供）：头颈部鳞状细胞癌（SCCHN）是美国和全球的严重医疗问题，是所有癌症中最致命的癌症之一，在美国，每年诊断出48,000多例新病例和15,000例死亡。 SCCHN与暴露于烟草致癌物显着相关。前吸烟者和活跃的吸烟者在烟草致癌的田间（尤其是口腔和喉咙）中仍处于侵袭性癌症的高风险。这些癌症通常从口腔内的小，通常没有注意到的病变开始，未经治疗的癌前口腔病变中有三分之一以上会发生恶性转化为鳞状细胞癌。尽管传统的手术程序，放疗和化学疗法的进步，但在过去的几十年中，SCCHN的总体存活率尚未得到显着提高。此外，尽管完全切除了手术，但这些癌前病变中很大一部分复发。在降低SCCHN和其他与烟癌相关的恶性肿瘤的发生率方面，可以在侵入性癌症发展之前实施的一种有效的预防方法。当前的建议旨在使用组合方法预防头部和颈部的预触发性病变。在80-90％的SCCHN，发育不良病变和SCCHN患者的组织学正常粘膜中，表皮生长因子受体（EGFR）的过表达已在SCCHN中发现，这表明EGFR上调代表了癌变的早期事件，并且可能是发展预防策略的重要目标。但是，EGFR抑制剂仅显示出适度的反应率作为单个药物。厄洛替尼与其他化学预防剂的组合可以通过协同生长抑制特性提高功效。但是，关键的挑战是确定可以提供协同作用的有效组合 生长抑制。我们假设，使用EGFR抑制剂Erlotinib与EGCG（一种多靶向天然化合物）的组合可以降低癌症的发病率，并极大地使患癌症患者高风险的患者受益。具体目标1的重点是这两种化合物之间的协同机理，特别着重于FOXO-P21/P27/BIM和MTOR-PS6信号传导及其对AKT和ERK的调节。特定目标2试图确定活检组织样品中选定的生物标志物的表达水平是否受到联合处理的好调节。 公共卫生相关性：活跃的和以前的吸烟者仍然处于烟草致癌田中侵袭性癌症的高风险 - 尤其是口腔和喉咙，以及一种化学预防的方法，非常需要减少烟草致癌物的数量，包括头部和颈部。该项目的重点是鉴定分子靶标，这对于EGFR Tki erlotinib和绿茶多酚EGCG的结合的协同化学预防效果至关重要。这种合并的化学预防治疗是阻止癌变的一种新型方法，并可能进一步影响并减少癌症的发生并有助于设计II期试验。