Identification of novel pathways for drug development for lung disease

Abstract

The invention provides the identification of oncogenic pathways activated in cytologically normal airway cells of individuals having or at risk of having lung disease, as well as specific gene expression patterns (biomarkers) associated with pathway activation. These biomarkers and pathways may provide prognostic and/or diagnostic indicators in lung disease, e.g., lung cancer. Additionally, these pathways and biomarkers may provide therapeutic targets for the treatment of lung disease, as well as markers for the assessment of treatment efficacy.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional application Ser. No. 60 / 994,643, filed Sep. 19, 2007, the entire teachings of which are incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]Work described herein was supported by funding from Grant Nos. NIH / NCI R01CA124640 and NIH / NIEHS U01ES016035. The U.S. Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Cigarette smoke is the dominant cause of lung cancer in the United States, accounting for an estimated 90% of all cases [1]. However, the damage caused by cigarette smoke is not limited solely to the lung, but rather constitutes a ‘field of injury’ throughout the entire respiratory tract [2-6]. An important product of the field of injury hypothesis is the ability to glean clinically relevant information from cells collected in regions of the respiratory tract, such as the bronchial airway, that can be obtained in a l...

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[0006]It has been previously demonstrated that gene expression profiling of cytologically normal bronchial airway epithelium reflects a field of injury in smokers that can serve as a sensitive and specific diagnostic biomarker for lung cancer. Using gene expression signatures defined by in vitro perturbation of specific oncogenic pathways, as described herein a significant increase of phosphatidylinositol 3-kinase (PI3K) pathway activity was identified in the cytologically normal airway of smokers with lung cancer (n=129), as well as in lung tumor tissue (n=107). To evaluate whether increased activity of PI3K occurs prior to the development of lung cancer, cytologically normal airway epithelia in high-risk smokers with moderate-severe dysplastic lesions in their airway (n=14) were profiled, and higher levels of PI3K pathway ge

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However, the damage caused by cigarette smoke is not limited solely to the lung, but

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