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.

头颈鳞状细胞癌 (SCCHN) 在美国是一个严重的医疗保健问题 各州和全世界。因此，开发使用特定天然或合成的预防方法 化学化合物（化学预防）对于降低 SCCHN 的发病率非常有必要。一些 化学预防方案已在临床前和临床环境中进行了测试，但没有有希望的方案 已被充分记录。在这项研究中，我们建议使用绿茶多酚 E 的组合 (PPE) 和厄洛替尼（特罗凯或 OSI-774），一种表皮生长因子的酪氨酸激酶抑制剂 (TKI) 受体（EGFR），预防头颈部晚期癌前病变。 PPE 和 EGFR-TKI 作为单一药物在多种癌症中显示出强大的抗癌活性和化学预防功效 类型，包括 SCCHN。我们的初步研究表明，表没食子儿茶素的组合 没食子酸酯（EGCG），一种从绿茶中提取的主要多酚，与厄洛替尼协同抑制 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。 周期停滞和细胞凋亡。此外，这种组合协同降低了 EGFR 和 AKT。 EGCG 和厄洛替尼还调节 E-的表达和细胞表面定位 钙粘蛋白，表明它们可能抑制恶性细胞的上皮间质转化（EMT） 上皮细胞。基于这些发现，我们假设 PPE 和厄洛替尼联合治疗 正如生物标志物表达所反映的，可以加性/协同地抑制患有以下疾病的患者的致癌作用： 头颈部癌前病变。为了检验这一假设，我们提出以下具体目标： (1) 了解EGCG（和/或PPE）联合治疗效果的潜在机制 和厄洛替尼对负责 SCCHN 进展和生存的信号转导途径的影响； (2) 至 对患有癌前病变的患者进行 PPE 和厄洛替尼联合治疗的 I 期试验 头部和颈部； (3) 鉴定患者标本中与该治疗相关的生物标志物并探索 所提出的生物标志物与临床和病理结果的相关变化。临床上 开发这种药物组合作为癌症预防方案可能有助于减少癌症 SCCHN 的发生率。通过识别肿瘤标志物可以进一步增强这一点，这些标志物可以充当 治疗效果指标。