Second Primary Tumor Prevention w/EGFR TKIs, COX-2 inhibitors Head & Neck Cancer

描述（由申请人提供）：早期（I/II期）头颈鳞状细胞癌（SCCHN）治疗失败的主要原因是第二原发肿瘤（SPT）的发展。最近，已经开发出几种针对特定分子途径的天然或合成化合物，用于治疗和预防癌症。作为预防 SPT 发展的新方法，我们建议对早期 SCCHN 患者进行一项临床试验，使用表皮生长因子受体 (EGFR) 的酪氨酸激酶抑制剂 (TKI) 和环氧合酶 2 抑制剂 (COX-2I) 两种药物的组合来预防 SCCHN 肿瘤发生的进展。我们认为，同时阻断这两个目标是一种新颖的方法，并且在初步数据中显示出对 SCCHN 的累加或协同抑制作用。我们将测试以下假设：1）EGFR-TKI 和 COX-2Is 联合使用，通过抑制细胞周期进程、诱导细胞凋亡和阻断血管生成来延迟或阻止 SPT 形成； 2）肿瘤细胞中COX-2的过度表达导致先天性和适应性免疫反应的免疫功能障碍，这是通过PGE2释放介导的并伴随肿瘤细胞上STAT-3的磷酸化。使用 EGFR-TKI 和 COX-2Is 抑制这些分子途径可恢复免疫反应性并改善抗肿瘤反应。为了检验这些假设，我们提出了以下具体目标： 目标 1，评估 EGFR-TKI（厄洛替尼）和 COX-2I（塞来昔布）联合方案降低早期（I/II 期）SCCHN 患者 SPT 发生和复发风险的安全性和有效性；目标2，通过使用来自参与临床试验的患者的肿瘤样本分析相关生物标志物，了解异常EGFR和COX-2介导的通路对SPT发展的贡献，并研究EGFR选择性TKIs和COX-2Is联合治疗对细胞周期进展、细胞凋亡和血管生成的影响；目标 3，在一系列实验中评估 EGFR 选择性 TKI 和 COX-2Is 组合对宿主免疫系统的体内和体外影响，这些实验旨在：a) 利用从参与临床试验的患者循环中分离的免疫细胞，b) 对用药物组合治疗的选定 SCCHN 细胞系与正常人淋巴细胞或其子集之间的相互作用进行离体建模。临床试验和生物标志物研究将采用各种方法进行，包括药代动力学研究、免疫组织化学、免疫印迹、RT-PCR、IMCPL 监测和统计分析。

DESCRIPTION (provided by applicant): The major cause of treatment failure in early stage (stage I/II) squamous cell carcinoma of the head and neck (SCCHN) is development of second primary tumors (SPTs). Recently, several natural or synthetic chemical compounds that target specific molecular pathways have been developed for use in treatment and prevention of cancer. As a novel approach to prevention of SPT developments, we are proposing a clinical trial for patients with early stage of SCCHN using a combination of two types of agents, tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptors (EGFR) and cyclooxygenase-2 inhibitor (COX-2I) to prevent progression of tumorigenesis of SCCHN. Simultaneously blocking these two targets, we believe, is a novel approach and shows additive or synergistic inhibitory effects for SCCHN in preliminary data. We will test the following hypotheses: 1) combination of EGFR-TKIs and COX-2Is to delay or prevent SPT formation by inhibition of cell cycle progression, induction of apoptosis, and blocking angiogenesis; 2) overexpression of COX-2 in tumor cells to lead to immune dysfunction of both innate and adaptive immune responses, which are mediated via PGE2 release and accompanied by STAT-3 phosphorylation on the tumor cells. Inhibition of these molecular pathways with EGFR-TKIs and COX-2Is leads to the restoration of immune reactivity and improved antitumor response. To test these hypotheses, we proposed the following specific aims: Aim 1, to evaluate the safety and efficacy of the combined EGFR-TKI (Erlotinib) and COX-2I (Celecoxib) regimen in reducing the risk of SPT development and recurrence in patients with early stage (stage I/II) SCCHN; Aim 2, to understand the contribution of abnormal EGFR and COX-2 mediated pathways to the development of SPT and to study effects of the treatment with combined EGFR selective TKIs and COX-2Is on the cell cycle progression, apoptosis, and angiogenesis by analyzing relevant biomarkers using tumor samples derived from patients who participate in the clinical trial; Aim 3, to evaluate in vivo and in vitro effects of the combination of EGFR-selective TKIs and COX-2Is on the immune system of the host in a series of experiments designed to: a) utilize immune cells isolated from the circulation of patients participating in the clinical trial and b) ex vivo modeling of interactions between the selected SCCHN cell lines treated with the drug combination and normal human lymphocytes or their subsets. The clinical trial and biomarker studies will be conducted with various methodologies, including pharmacokinetic studies, immunohistochemistry, immunoblot, RT-PCR, IMCPL monitoring, and statistical analyses.