TARGETING COX-2 AND EGFR SIGNALING IN ORAL CARCINOGENESIS

口腔癌发生过程中针对 COX-2 和 EGFR 信号传导

• 批准号: 6990021
• 负责人: REUBEN LOTAN
• 金额: $ 22.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990021
• 关键词: apoptosis; athymic mouse; biological signal transduction; biopsy; cancer prevention; carcinogenesis inhibitor; cell growth regulation; cell proliferation; chemoprevention; combination chemotherapy; epidermal growth factor; growth factor receptors; head /neck neoplasm; human tissue; immunocytochemistry; in situ hybridization; international cooperation; metastasis; mouth neoplasms; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; preneoplastic state; prostaglandin endoperoxide synthase; terminal nick end labeling; tissue /cell culture; western blottings

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, which afflicts more than 300,000 people worldwide and about 42,000 in the US annually and is associated with severe morbidity and <50% long-term survival. Strategies for prevention of HNSCC include identification of individuals at a high risk to develop such cancers (e.g., individuals with oral premalignant lesions) and to treat them with agents that can suppress the development of additional premalignant lesions and inhibit the development of oral cancer. Early events in the multistep oral carcinogenesis include activation of signaling or metabolic pathways that endow the cells with favorable growth and survival characteristics. Therefore, agents that can inhibit or reverse these changes by targeting molecularly defined pathways are potential novel candidates for cancer prevention and therapy. This project is based on the hypothesis that the arachidonic acid metabolizing enzyme cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR), which are both upregulated in oral premalignant lesions, are important for oral carcinogenesis and are excellent targets for intervention. Therefore, the long term objective of this project is the assess the potential of combinations of the COX-2 inhibitor Celecoxib and the irreversible EGFR inhibitor EKB-569 to act additively or synergistically to suppress prostaglandin production and inhibit EGFR signaling and thereby inhibit the growth or enhance apoptosis in premalignant oral keratinocytes and HNSCCs using in vitro and in vivo models. Normal oral keratinocytes and short- and long-term cultures of epithelial cells derived from dysplastic oral lesions will serve as an in vitro model to study mechanisms of oral carcinogenesis and assess the potential of the above agents. The specific aims are: 1) Analyze surgical specimens from patients enrolled in Project 1 at baseline and after treatment with celecoxib, EKB-569 or their combination for constitutive and treatment-modulated levels of the molecular targets of the agents and consequences of such modulation including changes in the COX-2 product prostaglandin E2 (PGE2) levels, cell proliferation marker and apoptosis; 2) To elucidate the mechanism by which PGE2 induces the proliferation of oral epithelial cells; 3) To establish short-term and long-term cultures of oral dysplastic cells in vitro and characterize the cells and to examine the response of the dysplastic cells as well as normal and premalignant oral keratinocytes and HNSCC cells to celecoxib, EKB-569 and their combinations; 4) To determine whether a therapeutic regimen combining celecoxib and EKB-569 is more effective at inhibiting the growth of HNSCC xenografts than either agent given alone.

头部和颈部鳞状细胞癌（HNSCC）是一种侵略性恶性肿瘤，在全球范围内遭受30万以上的人，在美国每年约有42,000人，与严重的发病率和长期生存有关。预防HNSCC的策略包括识别具有高风险的个人（例如，口腔前病变的个体），并与可以抑制发展的代理人对待他们 额外的预先病变并抑制口腔癌的发展。多步癌发生的早期事件包括激活信号传导或代谢途径，这些途径赋予细胞具有良好的生长和生存特征。因此，可以通过靶向分子定义的途径来抑制或逆转这些变化的药物是预防癌症和治疗的潜在新候选者。该项目基于以下假设 花生四烯酸代谢酶环氧酶-2（COX-2）和表皮生长因子受体（EGFR）在口腔前病变中都上调，对口服癌变非常重要，并且是干预的极好靶标。因此，该项目的长期目标是评估COX-2抑制剂Celecoxib和不可逆EGFR抑制剂EKB-569的组合的潜力使用体外和体内模型增强口服角质形成细胞和HNSCC的凋亡。源自发育不良的口服病变的上皮细胞的正常口服角质形成细胞和短期培养物将作为研究口服致癌机制的体外模型，并评估上述药物的潜力。具体目的是：1）分析 来自基线和塞来昔布治疗后，EKB-569的患者的手术标本，或将其组合用于本组成和治疗调节的药物分子靶标的水平以及这种调节的后果，包括COX-2产品Protostaglandin Protaglandin的变化E2（PGE2）水平，细胞增殖标记和凋亡； 2）阐明PGE2诱导口腔上皮细胞增殖的机制； 3）在体外建立口服异型症细胞的短期和长期培养物，并表征细胞，并检查发育不良细胞的反应以及正常和预启示性的口服角质形成细胞以及HNSCC细胞对Celecoxib，Ekb-569及其对Celecoxib及其的反应。组合； 4）确定结合塞来昔布和EKB-569的治疗方案是否比单独给出的任何药物更有效地抑制HNSCC异种移植物的生长。