Combinational Approaches to the Chemoprevention of Esophageal Cancer

描述(由申请人提供)： 食道癌是全球第六大常见恶性肿瘤，超过90%的病例是食管鳞癌。食道鳞状细胞癌的危险因素包括吸烟、饮酒、营养不足和摄入被各种真菌毒素污染的食物。食道鳞状细胞癌比其他类型的胃肠道恶性肿瘤生长更快，患者预后非常差。虽然手术、化疗和放射治疗单独或联合使用，但该病的总体5年生存率仍然很低，从5%到15%不等。为了减少食道癌的发病率，通过饮食和/或化学干预进行癌症化学预防将是一种合乎逻辑和实际的方法。已经测试了许多化合物；然而，到目前为止，试验并没有导致食道癌发病率的下降。迫切需要确定保护剂，以便在与食道癌风险增加相关的个人中预防这种疾病。我们研究的长期目标是开发机制驱动的、安全有效的预防策略，以降低高危人群中食道癌的发病率。N-亚硝基甲基苄胺(NMBA)诱导的大鼠食道癌的临床前模型已被广泛用于研究食道癌的发生机制和评价潜在的化学预防药物的效果。食道鳞状细胞癌的多阶段演变，从正常到增生、不典型增生和乳头状瘤，是应用化学预防策略的理想选择。在这项提案中，我们概述了我们开发食道癌化学预防的组合方法的战略。我们的中心假设是，环氧合酶-2(COX-2)抑制剂、塞来昔布、诱导型一氧化氮合酶(INOS)抑制剂、S、S的1，4-苯基-双(1，2-乙二基)双-异硫脲(PBIT)和冻干黑树莓(BRB)的组合将在提高抗肿瘤疗效的同时将毒性降至最低。其具体目的是：1.建立COX-2和诱导型一氧化氮合酶抑制剂联合应用提高食道癌预防效果的策略；2.建立纯化合物(S)和天然食品联合应用提高食道癌预防效果的策略，并探讨其作用的细胞和分子机制；3.探讨丝裂原活化蛋白激酶和核因子：B信号通路在NMBA诱导的大鼠食道癌发生中的作用。总体而言，这项假说驱动的临床前研究的成功结果将为开发与可能在食道癌化学预防的人类临床试验中具有协同活性的药物的组合提供重要的信息和理论基础。公共卫生相关性：该项目的总体目标是评估联合治疗食道癌的有效性，研究这些药物的机制基础，并使用与人类食管鳞癌高度相似的大鼠临床前模型来确定食道癌发生的细胞和分子生物标志物。

DESCRIPTION (provided by applicant): Esophageal cancer is the 6th most common malignant neoplasm worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (SCC). Risk factors for esophageal SCC include tobacco use, alcohol consumption, nutritional deficiency, and intake of food contaminated with various mycotoxins. Esophageal SCC grows more quickly than other kinds of gastrointestinal malignancies and patients with this disease have a very poor prognosis. Although surgery, chemotherapy, and radiotherapy alone or combined are used, the overall 5-year survival rate for this disease is still very low, ranging from 5% to 15%. To decrease the incidence of esophageal cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Numerous compounds have been tested; however, the trails to date have not resulted in a decrease of esophageal cancer incidence. There is an urgent need to identify protective agents, which can prevent this disease in the individuals associated with increasing esophageal cancer risk. The long-term goal of our studies is to develop mechanism-driven safe and effective prevention strategies for reducing the incidence of esophageal cancer in high-risk populations. N-nitrosomethylbenzylamine (NMBA)- induced rat preclinical model of esophageal cancer has been used extensively to investigate the mechanisms of esophageal carcinogenesis and to evaluate the efficacy of potential chemopreventive agents. The multistage evolution of esophageal SCC, from normal to hyperplasia, dysplasia and papilloma, is ideal for the application of chemoprevention strategies. In this proposal, we outline our strategy to develop combinational approaches to the chemoprevention of esophageal cancer. Our central hypothesis is that combination of cyclooxygenase-2 (COX-2) inhibitor, celecoxib, inducible nitric oxide synthase (iNOS) inhibitor, S,S'-1,4- phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), and freeze-dried black raspberries (BRB) will increase efficacy against tumor development while minimizing toxicity in NMBA-rat preclinical model. The specific aims are: 1. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of COX-2 and iNOS inhibitors; 2. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of pure compound(s) and natural food product and to determine the cellular and molecular mechanisms of their actions; 3. To investigate the roles of mitogen-activated protein kinase (MAPK) and nuclear factor :B (NF:B) pathways in NMBA-induced tumorigenesis in the rat esophagus. Overall, a successful outcome of this hypothesis-driven preclinical study will provide important information and rationale to develop a combination with agents that may have synergistic activity in human clinical trials of chemoprevention of esophageal cancer. PUBLIC HEALTH RELEVANCE: The overall objective of this project is to evaluate the efficacy of combinational approaches against esophageal cancer development, to investigate the mechanistic basis of these agents, and to identify cellular and molecular biomarkers of esophageal tumorigenesis using a rat preclinical model, which is highly analogous to human esophageal squamous cell carcinoma.