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The Hedgehog Pathway and Lung Cancer Prevention

刺猬通路与肺癌预防

基本信息

批准号：
7388334
负责人：
ETHAN DMITROVSKY
金额：
$ 8万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/7388334
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

项目摘要

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）：