The Hedgehog Pathway and Lung Cancer Prevention

刺猬通路与肺癌预防

• 批准号: 7500805
• 负责人: ETHAN DMITROVSKY
• 金额: $ 8万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500805
• 关键词: Affect; Cancer cell line; Cell Line; Cells; Chemoprevention; Chromosomal Instability; Clinic; Collaborations; Cyclin D1; Cyclin E; Development; Dose; Engineering; Epithelial Cells; Erinaceidae; Future; Gene Targeting; Grant; Growth; Human; In Vitro; Incidence; Learning; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; PTCH gene; Pathway interactions; Pharmacodynamics; Premalignant; Proteins; Public Health; Publishing; Radiation therapy; Relative (related person); Reporting; Repression; Resistance; Resources; Societies; Staging; Tail; Transgenic Model; Transgenic Organisms; Translating; United States National Academy of Sciences; United States National Institutes of Health; Veins; Woman; Work; cancer cell; cancer chemoprevention; chemotherapy; cyclopamine; dosage; improved; in vivo; loss of function; lung cancer prevention; lung carcinogenesis; men; mouse model; multicatalytic endopeptidase complex; novel; prevent; promoter; surfactant

DESCRIPTION (provided by applicant): Lung cancer is the most common lethal malignancy for men and women. With the absence of curative therapy for advanced stage lung cancer, chemoprevention is an appealing strategy to combat this major public health problem. This NIH R03 application responds to PAR-06-313: Small Grants in Cancer Chemoprevention and takes advantage of novel transgenic human cyclin E mouse models that we engineered to target expression in the lung with the human surfactant C (SP-C) promoter. Wild-type and proteasome-degradation resistant cyclin E lines were each engineered. Notably, these lines developed chromosome instability, pre-malignancy, single or multiple lung adenocarcinomas and even metastases. Unexpectedly, a common feature of these lines was activation of the hedgehog (Hh) pathway in pre-malignant and malignant lung lesions. These findings build on our prior published work that Hh pathway activation frequently occurs in non-small cell lung cancer. These unique resources and an extensive panel of lung cancer cell lines will be used to explore Hh pathway targeting in lung cancer chemoprevention using the antagonist cyclopamine. Two specific aims are: (1) to comprehensively explore growth suppressive effects of cyclopamine in human and murine immortalized and malignant lung epithelial cell lines (including those engineered with Hh pathway gain or loss function and novel lung cancer cell lines from transgenic cyclin E lung tumors) and (2) to extend studies to the in vivo setting by learning whether cyclopamine suppresses lung carcinogenesis in mice and even prevents transgenic cyclin E lines from developing pre-malignant or malignant lung lesions. These findings would provide a strong rationale to translate work into the clinic in the future. Given the major public health impact from successful conclusion of these aims, we are eager to pursue these studies.

描述（由申请人提供）： 肺癌是男性和女性最常见的致命恶性肿瘤。由于晚期肺癌缺乏治疗方法，化学预防是解决这一重大公共卫生问题的一种有吸引力的策略。此 NIH R03 应用响应 PAR-06-313：癌症化学预防小额资助，并利用新型转基因人细胞周期蛋白 E 小鼠模型，我们将其设计为使用人表面活性剂 C (SP-C) 启动子在肺部进行靶向表达。野生型和蛋白酶体降解抗性细胞周期蛋白 E 系均经过工程改造。值得注意的是，这些细胞系出现了染色体不稳定、癌前病变、单发或多发肺腺癌甚至转移。出乎意料的是，这些细胞系的一个共同特征是在癌前和恶性肺部病变中激活刺猬蛋白（Hh）通路。这些发现建立在我们之前发表的研究基础上，即 Hh 通路激活经常发生在非小细胞肺癌中。这些独特的资源和广泛的肺癌细胞系组将用于探索使用拮抗剂环杷明进行肺癌化学预防的 Hh 通路靶向。两个具体目标是：(1) 全面探索环杷明对人类和小鼠永生化和恶性肺上皮细胞系（包括 Hh 途径获得或丧失功能的细胞系和来自转基因细胞周期蛋白 E 肺肿瘤的新型肺癌细胞系）的生长抑制作用；(2) 通过了解环杷明是否抑制小鼠甚至肺癌的发生，将研究扩展到体内环境 防止转基因细胞周期蛋白 E 系发生癌前或恶性肺部病变。这些发现将为未来将工作转化为临床提供强有力的理由。鉴于成功实现这些目标对公共卫生产生的重大影响，我们渴望进行这些研究。