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

描述(申请人提供)：早期(I/II期)头颈部鳞状细胞癌(SCCHN)治疗失败的主要原因是第二原发肿瘤(SPT)的发展。最近，针对特定分子途径的几种天然或合成化合物已被开发用于癌症的治疗和预防。作为一种预防SPT发展的新方法，我们提议对早期SCCHN患者进行临床试验，联合使用两种药物，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)以防止SCCHN的肿瘤发生进展。我们认为，同时阻断这两个靶点是一种新的方法，在初步数据中显示出对SCCHN的相加或协同抑制作用。我们将检验以下假设：1)EGFR-TKI和COX-2的结合是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防止SPT的形成；2)COX-2在肿瘤细胞中过表达，导致先天和获得性免疫反应的免疫功能障碍，这是通过PGE2释放介导的，并伴随着肿瘤细胞上STAT-3的磷酸化。用EGFR-TKIs和COX-2IS抑制这些分子通路可以恢复免疫反应，改善抗肿瘤反应。为了验证这些假说，我们提出了以下具体目标：目的1，评价EGFR-TKI(Erlotinib)联合COX-2I(塞来昔布)方案在降低早期(I/II期)SCCHN患者SPT发生和复发风险方面的安全性和有效性；目的2，了解EGFR和COX-2介导的异常通路在SPT发生发展中的作用，并通过对参与临床试验的患者肿瘤标本进行相关生物标志物分析，研究EGFR选择性TKI和COX-2联合治疗对细胞周期进展、细胞凋亡和血管生成的影响；目的：通过一系列实验评价EGFR选择性TKI和COX-2IS对宿主免疫系统的影响。实验的目的是：a)利用从参与临床试验的患者循环中分离的免疫细胞；b)体外模拟经该药物组合处理的SCCHN细胞株与正常人淋巴细胞或其亚群之间的相互作用。临床试验和生物标记物研究将采用各种方法，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.