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。一个有效的预防方法,可以实现在侵入性癌症的发展是非常可取的减少烟草carcinogen-related恶性肿瘤和其他头颈部鳞状细胞癌的发病率。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