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: 7666221
• 负责人: DONG M SHIN
• 金额: $ 32.88万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666221
• 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; 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; 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; design; improved; in vivo; inhibitor/antagonist; monocyte; neoplastic cell; novel; novel strategies; overexpression; 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（由申请人提供）：早期治疗失败的主要原因（I/II期）头颈部鳞状细胞癌（SCCHN）是第二个原发性肿瘤（SPTS）的发展。最近，已经开发了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。作为一种新型的预防SPT发展方法，我们正在为SCCHN早期患者提出一项临床试验，使用两种类型的剂，酪氨酸激酶抑制剂（TKI）的表皮生长因子受体（EGFR）和环氧酶-2抑制剂（COX-2I）的临床试验，以预防Scchn的糖尿病。我们认为，同时阻止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的加性或协同抑制作用。我们将检验以下假设：1）EGFR-TKIS和COX-2I的组合，以延迟或防止SPT形成，通过抑制细胞周期进展，诱导凋亡和阻断血管生成； 2）COX-2在肿瘤细胞中的过表达导致先天性和适应性免疫反应的免疫功能障碍，这些反应是通过PGE2释放介导的，并伴有肿瘤细胞上的Stat-3磷酸化。用EGFR-TKI和COX-2IS抑制这些分子途径会导致免疫反应性恢复并改善抗肿瘤反应。为了检验这些假设，我们提出了以下具体目的：目标1，以评估联合EGFR-TKI（Erlotinib）（Erlotinib）和Cox-2I（Celecoxib）方案的安全性和功效，以降低患有早期（I/II）SCCHN患者的SPT发育风险和重新恢复的风险；目的2，以了解异常EGFR和COX-2介导的途径对SPT的发展的贡献，并通过使用从参与临床试验的患者分析的患者分析使用肿瘤的患者分析相关的生物标记样本来研究使用EGFR选择性TKI和COX-2I对细胞周期进展，凋亡和血管生成的影响； 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.临床试验和生物标志物研究将使用各种方法进行，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。