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

使用 EGFR TKI、COX-2 抑制剂进行第二级肿瘤预防 负责人

• 批准号: 7278139
• 负责人: DONG M SHIN
• 金额: $ 32.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-18 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278139
• 关键词: 17p; Aneuploidy; Angiogenesis Inhibitors; Antitumor Response; Apoptosis; Biological; Biological Markers; Blood Circulation; Carcinogens; Cell Cycle; Cell Cycle Progression; Cell Line; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; Coxibs; Data; Dendritic Cells; Development; Diagnosis; Diagnostic; Dinoprostone; Disease-Free Survival; Drug Combinations; Drug Kinetics; End Point; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunoblotting; Immunohistochemistry; In Vitro; Induction of Apoptosis; Laboratories; Lead; Living Wills; Lymphocyte; Measures; Mediating; Methodology; Modeling; Molecular; Monitor; Natural Killer Cells; Outcome; PTGS2 gene; Pathway interactions; Patients; Phosphorylation; Prevention; Prevention approach; Preventive; Primary Neoplasm; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins E; Protein Overexpression; Rate; Recurrence; Relative (related person); Research Personnel; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Risk; Safety; Sampling; Series; Squamous cell carcinoma; Staging; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Failure; Treatment Protocols; Tyrosine Kinase Inhibitor; angiogenesis; anticancer activity; cancer prevention; cancer therapy; celecoxib; cell growth; cyclooxygenase 1; design; improved; in vivo; inhibitor/antagonist; monocyte; neoplastic cell; novel; novel strategies; pre-clinical; prevent; programs; research study; response; restoration; treatment effect; tumor; tumor progression; tumorigenesis

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.

描述（由申请方提供）：早期（I/II期）头颈部鳞状细胞癌（SCCHN）治疗失败的主要原因是发生第二原发肿瘤（SPT）。最近，已经开发了几种靶向特定分子途径的天然或合成化合物用于治疗和预防癌症。作为一种预防SPT发展的新方法，我们提出了一项临床试验，用于早期SCCHN患者，使用两种类型的药物，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（考克斯-2 I）的组合，以预防SCCHN肿瘤发生的进展。我们认为，同时阻断这两个靶点是一种新的方法，并在初步数据中显示出对SCCHN的累加或协同抑制作用。我们将检验以下假设：1）EGFR-TKI和考克斯-2 Is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预防SPT形成; 2）肿瘤细胞中考克斯-2过表达，导致先天性和适应性免疫应答的免疫功能障碍，这些免疫功能障碍通过PGE 2释放介导，并伴随肿瘤细胞上STAT-3磷酸化。用EGFR-TKI和考克斯-2 I抑制这些分子途径导致免疫反应性的恢复和抗肿瘤应答的改善。为了检验这些假设，我们提出了以下具体目标：目标1，评价联合EGFR-TKI的安全性和有效性（厄洛替尼）和考克斯-2 I塞来昔布方案降低早期SPT患者发生和复发风险的研究（I/II期）SCCHN;目标二，了解异常EGFR和考克斯的作用，2介导的SPT发生的途径，并研究EGFR选择性TKI和考克斯-2 Is联合治疗对细胞周期进展、细胞凋亡、目的3，在一系列实验中评价EGFR选择性TKI和考克斯-2 I组合对宿主免疫系统的体内和体外作用，所述实验设计为：a）利用从参与临床试验的患者的循环中分离的免疫细胞，和B）用药物组合处理的所选SCCHN细胞系与正常人淋巴细胞或其亚群之间的相互作用的离体建模。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。