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

头颈部鳞状细胞癌(SCCHN)在美国是一个严重的医疗问题 美国和世界各地。因此，开发使用特定的天然或人工合成的预防方法 为了减少SCCHN的发病率，化学预防是非常必要的。几个 化疗预防方案已经在临床前和临床环境中进行了测试，但没有前景看好的方案。 已经被很好地记录下来了。在本研究中，我们建议使用绿茶多酚E的组合 (PPE)和埃洛替尼(Tarceva或OSI-774)，表皮生长因子的酪氨酸激酶抑制剂(TKI) 受体(EGFR)，用于预防晚期头颈部癌前病变。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效果 类型，包括SCCHN。我们的初步研究表明，表没食子儿茶素 从绿茶中提取的主要多酚-没食子酸酯(EGCG)与厄洛替尼协同抑制 SCCHN细胞在体内外的生长情况。这种抑制作用与细胞的诱导有关。 细胞周期停滞和细胞凋亡。此外，这种结合协同降低了磷酸化水平。 EGFR和AKT。EGCG和厄洛替尼也调节E-受体的表达和细胞表面的定位 钙粘附素，提示它们可能抑制恶性上皮细胞向间充质细胞转化(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 通过生物标记物的表达，是否可以相加/协同抑制癌症的发生 头部和颈部的癌前病变。为了验证这一假设，我们提出了以下具体目标： (1)了解EGCG(和/或PPE)联合治疗效果的潜在机制 和厄洛替尼在负责SCCHN进展和生存的信号转导通路上；(2) 进行PPE和厄洛替尼联合治疗乳腺癌癌前病变的I期试验 (3)在患者的标本中寻找与这种治疗相关的生物标志物，并探索 建议的生物标志物与临床和病理结果的相关性变化。临床部 这种药物组合作为癌症预防方案的开发可能有助于减少 SCCHN的发病率。这可能会通过识别肿瘤标记物来进一步加强，这些标记物可以作为 治疗效果的指标。

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.