CHEMOPREVENTION WITH GREEN TEA POLYPHENON E (PPE) AND EGFR-TKIs IN HEAD AND NECK

使用绿茶多酚 E (PPE) 和 EGFR-TKI 在头颈部进行化学预防

• 批准号: 7300623
• 负责人: DONG M SHIN
• 金额: $ 39.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300623
• 关键词: AKT Signaling Pathway; Affect; Aftercare; Apoptosis; Biological Markers; Cell Adhesion Molecules; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Line; Cell surface; Cell-Cell Adhesion; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Clinic; Clinical; Clinical Research; Combined Modality Therapy; Data; Development; Dose-Limiting; Drug Kinetics; E-Cadherin; Electrocardiogram; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigallocatechin Gallate; Epithelial; Erlotinib; Future; Green tea; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Healthcare; In Vitro; Incidence; Insulin-Like-Growth Factor I Receptor; Laminin Receptor-1; Lesion; Maize; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Moon; PI3K/AKT; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphorylation; Polyphenon E; Premalignant; Preparation; Preventive; Proto-Oncogene Proteins c-akt; Radiosurgery; Regulation; Research Personnel; Safety; Signal Pathway; Signal Transduction Pathway; Solid Neoplasm; Specimen; Squamous cell carcinoma; Standards of Weights and Measures; Survival Rate; Testing; Toxic effect; Treatment Efficacy; Treatment Protocols; Tumor Markers; Tyrosine Kinase Inhibitor; United States; Zea mays; anticancer activity; base; cancer therapy; cancer type; carcinogenesis; chemotherapy; concept; epicatechin; epithelial to mesenchymal transition; gallocatechol; improved; in vivo; polyphenol; pre-clinical; prevent; programs; response; small molecule; toe corn

Squamous cell carcinoma of the head and neck (SCCHN) is a serious healthcare problem in the United States and worldwide. Thus, the development of preventive approaches using specific natural or synthetic chemical corn-pounds (chemoprevention) is highly desirable to reduce the incidence of SCCHN. Several chemo-pre-ventive regimens have been tested in preclinical and clinical settings, but no promising regimens have been well documented. In this study, we propose to use a combination of green tea polyphenon E (PPE) and erlotinib (Tarceva or OSI-774), a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), to prevent advanced premalignant lesions of the head and neck. Both PPE and EGFR-TKI have shown strong anticancer activity and chemopreventive efficacy as single agents in a variety of cancer types, including SCCHN. Our preliminary studies have shown that the combination of epigallocatechin gallate (EGCG), a major polyphenol extracted from green tea, with erlotinib synergistically inhibited the growth of SCCHN cells in vitro and in vivo. This inhibitory effect was associated with the induction of cell cycle arrest and apoptosis. Furthermore, this combination cooperatively reduced phosphorylation levels of EGFR and AKT. Both EGCG and erlotinib also regulate expression and cell surface localization of E- cadherin, suggesting that they may inhibit epithelial to mesenchymal transition (EMT) of the malignant epithelial cells. Based on these findings, we hypothesize that combined treatment with PPE and erlotinib can additively/synergistically inhibit carcinogenesis, as reflected by biomarker expression, in patients with premalignant lesions of the head and neck. To test this hypothesis we propose the following specific aims: (1) To under-stand the underlying mechanisms of the effect of combined treatment with EGCG (and/or PPE) and erlotinib on signal transduction pathways responsible for SCCHN progression and survival; (2) To conduct a phase I trial of combined treatment with PPE and erlotinib in patients with premalignant lesions of the head and neck; (3) To identify biomarkers relevant for this treatment in patients' specimens and explore correlative alterations in the proposed biomarkers with clinical and pathological findings. The clinical development of this combination of agents as a cancer preventive regimen may contribute to reducing the incidence of SCCHN. This may be further enhanced by the identification of tumor markers that can serve as indicators for treatment efficacy.

头颈部鳞状细胞癌（SCCHN）是曼联的严重医疗问题 国家和全球。因此，使用特定自然或合成的预防方法开发 化学玉米块（化学预防）非常需要减少SCCHN的发生率。一些 在临床前和临床环境中已经测试了化学释放方案，但没有有希望的方案 已经有充分的记录。在这项研究中，我们建议使用绿茶多形元素E的组合 （PPE）和Erlotinib（Tarceva或OSI-774），表皮生长因子的酪氨酸激酶抑制剂（TKI） 受体（EGFR），以防止头部和颈部的晚期预临床病变。 PPE和EGFR-TKI都 已经显示出强烈的抗癌活性和化学预防功效，作为多种癌症的单一药物 类型，包括SCCHN。我们的初步研究表明，表瓜蛋白的结合 食物酸酯（EGCG）是一种从绿茶中提取的主要多酚，erlotinib协同抑制了 SCCHN细胞在体外和体内的生长。这种抑制作用与细胞的诱导有关 周期停滞和凋亡。此外，这种组合合作降低了磷酸化水平 EGFR和AKT。 EGCG和Erlotinib都调节E-的表达和细胞表面定位 钙粘蛋白，表明它们可能抑制上皮对恶性肿瘤的间质转变（EMT） 上皮细胞。基于这些发现，我们假设将治疗与PPE和Erlotinib结合在一起 在生物标志物表达反映的患者中，可以在附加/协同上抑制癌变。 头部和颈部的预先病变。为了检验这一假设，我们提出了以下特定目的： （1）低于EGCG（和/或PPE）联合处理效果的基本机制 以及负责SCCHN进展和存活的信号转导途径的厄洛替尼； （2）至 对患有前病变的患者进行PPE和Erlotinib联合治疗的I期试验 头和脖子； （3）识别患者标本中与该治疗相关的生物标志物并进行探索 具有临床和病理发现的拟议生物标志物的相关改变。临床 这种代理作为癌症预防疗法的组合的发展可能有助于减少 SCCHN的发病率。通过识别可以用作的肿瘤标记物可以进一步增强这 治疗功效的指标。