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)是一种侵袭性较强的恶性肿瘤，全球每年有30多万人罹患此病，美国每年约有42,000人罹患此病，并与严重的发病率和50%的长期存活率有关。预防HNSCC的策略包括识别患此类癌症的高危个体(例如，患有口腔癌前病变的个体)，并用能够抑制其发展的药物进行治疗。 增加癌前病变，抑制口腔癌的发展。口腔多步骤癌变的早期事件包括信号或代谢通路的激活，这些通路赋予细胞良好的生长和生存特征。因此，通过靶向分子定义的通路来抑制或逆转这些变化的药物是潜在的癌症预防和治疗的新候选药物。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(COX-2)和表皮生长因子受体(EGFR)在口腔癌前病变中表达上调，在口腔癌的发生中起重要作用，是很好的干预靶点。因此，该项目的长期目标是评估COX-2抑制剂塞来昔布和不可逆转的EGFR抑制剂EKB-569联合作用的可能性，以抑制前列腺素的产生，抑制EGFR信号转导，从而通过体外和体内模型抑制癌前口腔角质形成细胞和HNSCCs的生长或促进凋亡。正常口腔角质形成细胞和口腔异型病变上皮细胞的短期和长期培养将作为研究口腔癌变机制和评估上述因素的潜力的体外模型。具体目标是：1)分析 项目1患者的手术标本在基线和塞来昔布、EKB-569或其组合治疗后，用于药物分子靶标的构成和治疗调节水平以及这种调节的后果，包括COX-2产物前列腺素E2(PGE2)水平、细胞增殖标志物和细胞凋亡的变化；2)阐明PGE2诱导口腔上皮细胞增殖的机制；3)建立口腔发育不良细胞的体外短期和长期培养并鉴定细胞，并检测异常增生细胞、正常和癌前角质形成细胞和HNSCC细胞对塞来昔布、EKB-569及其组合的反应；4)确定塞来昔布和EKB-569联合用药对抑制HNSCC移植瘤生长是否比单用任何一种药物更有效。