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

基本信息

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
项目类别：
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

项目摘要

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）：头颈鳞状细胞癌 (SCCHN) 是美国和全世界的一个严重的医疗保健问题，是所有癌症中最致命的一种，每年诊断出超过 48,000 例新病例，导致 15,000 例死亡在美国。 SCCHN 与接触烟草致癌物显着相关。无论是前吸烟者还是活跃吸烟者，在接触烟草致癌物的部位（尤其是口腔和喉部）仍然面临患侵袭性癌症的高风险。这些癌症通常始于口腔内小的、常常被忽视的病变，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。尽管传统外科手术、放疗和化疗取得了进步，但过去几十年来 SCCHN 的总体生存率并未显着提高。此外，尽管完全手术切除，但大部分癌前病变仍会复发。非常需要一种可以在侵袭性癌症发生之前实施的有效预防方法，以减少 SCCHN 和其他与烟草致癌物相关的恶性肿瘤的发病率。目前的提案旨在采用组合方法预防头部和颈部的癌前病变。在 80-90% 的 SCCHN、SCCHN 患者的发育不良病变和组织学正常粘膜中发现表皮生长因子受体 (EGFR) 过度表达，表明 EGFR 上调代表癌发生的早期事件，并可能作为癌症发生的重要靶点。干预制定预防策略。然而，EGFR 抑制剂作为单一药物仅表现出适度的反应率。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来提高疗效。然而，关键的挑战是找到一种有效的组合，可以提供协同作用生长抑制。我们推测，结合使用 EGFR 抑制剂厄洛替尼与多靶点天然化合物 EGCG 可以降低癌症发病率，并使癌症高危患者受益匪浅。具体目标 1 重点关注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-pS6 信号传导及其受 AKT 和 ERK 的调节。具体目标 2 旨在确定活检组织样本中所选生物标志物的表达水平是否受到联合治疗的有利调节。公共卫生相关性：无论是吸烟者还是戒烟者，在接触烟草致癌物的部位（尤其是口腔和喉部）仍面临罹患侵袭性癌症的高风险，因此非常需要采取化学预防方法来减少与烟草致癌物相关的恶性肿瘤（包括头部和颈部）的数量。脖子。该项目的重点是确定对 EGFR TKI 厄洛替尼和绿茶多酚 EGCG 组合的协同化学预防效力至关重要的分子靶点。这种联合化学预防治疗是一种阻止癌症发生的新方法，可能会进一步影响和降低癌症发病率，并有助于设计 II 期试验。