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Identification of novel pathways for drug development for lung disease

a technology of lung disease and drug development, applied in the field of identification of novel pathways for lung disease, can solve the problems of cigarette smoke, achieve the effects of reducing pi3k activity, increasing the activity of the phosphatidylinositol 3-kinase (pi3k) pathway, and increasing the expression of the pi3k pathway gen

Inactive Publication Date: 2009-07-23
TRUSTEES OF BOSTON UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[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 gene expression were found as compared to the airway epithelium from healthy smokers without dysplasia (n=11). Further, PI3K activity was decreased in the airway of high-risk smokers who had significant regression of dysplasia following treatment with the chemoprophylactic agent myo-inositol (n=10). In vitro dilution experiments confirmed that myo-inositol inhibits the PI3K pathway, which not only proposes a mechanism of action for myo-inositol, but also reflects a potential therapeutic relationship between PI3K pathway activity and regression of airway dysplasia. Together, these findings suggest that deregulation of the PI3K pathway is an early, measurable and reversible step in the development of lung cancer, and that airway gene expression profiling in smokers may enable personalized approaches to chemoprophylaxis and therapy.

Problems solved by technology

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].

Method used

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  • Identification of novel pathways for drug development for lung disease
  • Identification of novel pathways for drug development for lung disease
  • Identification of novel pathways for drug development for lung disease

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Embodiment Construction

[0028]Based on the concept that genomic changes in the epithelial cells that line the entire respiratory tract reflect host response to and damage from cigarette smoke, a better understanding of the early events leading to tumorigenesis may be gained by identifying which pathways are deregulated in the airway of smokers with or at risk for having lung cancer. One approach to assess pathway activity uses gene expression data to link in vitro activation of an isolated signaling pathway to predict status of that pathway in patient samples. This approach has been successful at predicting pathway status in cell lines as well as tumors where the initiation event is known [13]. A strength of in vitro defined pathway signatures is that they are capable of identifying pathway activity at the gene expression level, allowing the measurement of multiple pathways using a single microarray experiment. Further, gene expression based predictions of pathway activity have been found to correlate sign...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/05C12Q1/68C40B30/04C40B40/08A61P35/00
CPCG01N2800/50C12Q2600/106C12Q1/6886G01N33/57423A61K31/047A61K31/5377A61P11/00A61P35/00A61P43/00C12Q1/485C12Q1/6809C12Q2600/158C12Q2600/16G01N2333/91205G01N2800/7028
Inventor BRODY, JEROME S.SPIRA, AVRUMGUSTAFSON, ADAMBILD, ANDREA
Owner TRUSTEES OF BOSTON UNIV
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