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.

头颈部鳞状细胞癌（HNSCC）是一种侵袭性恶性肿瘤，全世界每年有超过300，000人患病，美国每年约有42，000人患病，并且与严重的发病率和<50%的长期生存率相关。预防HNSCC的策略包括鉴定处于发展此类癌症的高风险的个体（例如，患有口腔癌前病变的个体），并用能够抑制口腔癌前病变发展的药剂治疗它们。 额外的癌前病变和抑制口腔癌的发展。在多步骤的口腔癌发生的早期事件包括激活信号或代谢途径，赋予细胞有利的生长和存活特性。因此，能够通过靶向分子定义的途径抑制或逆转这些变化的药物是癌症预防和治疗的潜在新候选药物。这个项目是基于这样一个假设， 花生四烯酸代谢酶环氧合酶-2（考克斯-2）和表皮生长因子受体（EGFR）在口腔癌前病变中均被上调，它们对于口腔癌的发生是重要的，并且是极好的干预靶点。因此，本项目的长期目标是使用体外和体内模型评估考克斯-2抑制剂塞来昔布和不可逆EGFR抑制剂EKB-569的组合在抑制前列腺素产生和抑制EGFR信号传导从而抑制恶变前口腔角质形成细胞和HNSCC的生长或增强细胞凋亡方面的相加或协同作用的潜力。正常的口腔角质形成细胞和短期和长期培养的上皮细胞来源于发育不良的口腔病变将作为一个体外模型，研究口腔癌发生的机制，并评估上述代理商的潜力。具体目标是：1）分析 基线时和塞来昔布、EKB-569或其组合治疗后入组项目1的患者的手术标本，以确定药物分子靶点的组成性和治疗调节水平以及这种调节的结果，包括考克斯-2产物前列腺素E2（PGE 2）水平、细胞增殖标志物和细胞凋亡的变化; 2）探讨PGE 2诱导口腔上皮细胞增殖的机制;（3）建立短期和长期的口腔异型增生细胞的体外培养和表征细胞，并检查异型增生细胞以及正常和癌前口腔细胞的反应。角化细胞和HNSCC细胞对塞来昔布、EKB-569及其组合的作用; 4）确定塞来昔布和EKB-569组合的治疗方案是否比单独给予的任一药剂在抑制HNSCC异种移植物的生长方面更有效。