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.

1 . A method of identifying an individual at increased risk of lung disease, comprising determining the activation status of the PI3K pathway in a cytologically normal airway epithelial cell from said individual, wherein activation of the PI3K pathway is indicative that said individual is at increased risk of lung disease as compared with an individual in whom the PI3K pathway is not activated. 
   
   
       2 . A method according to  claim 1  wherein the individual is a smoker. 
   
   
       3 . A method according to  claim 1  wherein the individual is a non-smoker. 
   
   
       4 . A method according to  claim 1  wherein the lung disease is lung cancer. 
   
   
       5 . A method according to  claim 1  wherein the activation status of the PI3K pathway is determined using gene expression data for one or more biomarkers of the PI3K pathway. 
   
   
       6 . A method according to  claim 5  wherein at least one of said one or more biomarkers is a gene which is increased upon PI3K activation. 
   
   
       7 . A method according to  claim 5  wherein at least one of said one or more biomarkers is a gene which is decreased upon PI3K activation. 
   
   
       8 . A method according to  claim 5  wherein at least one of said one or more biomarkers is a gene which is upstream of PI3K activation. 
   
   
       9 . A method according to  claim 5  wherein the gene expression data for said one or more biomarkers of the PI3K pathway is obtained using an oligonucleotide microarray. 
   
   
       10 . A method according to  claim 1  wherein the activation status of the PI3K pathway is determined using one or more gene expression products of one or more biomarkers of the PI3K pathway. 
   
   
       11 . A method according to  claim 1  wherein the activation status of the PI3K pathway is determined by assessing the activation of IGF1R, wherein activation of IGF1R is indicative of activation of the PI3K pathway. 
   
   
       12 . A method according to  claim 1  wherein the activation status of the PI3K pathway is determined by assessing the activation of PKC, wherein activation of PKC is indicative of activation of the PI3K pathway. 
   
   
       13 . A method of identifying an individual at increased risk of lung disease, comprising determining the activation status of PKC in a cytologically normal airway epithelial cell from said individual, wherein activation of PKC is indicative that said individual is at increased risk of lung disease as compared with an individual in whom PKC is not activated. 
   
   
       14 . A method of identifying an individual at increased risk of lung disease, comprising determining the activation status of IGF1R in a cytologically normal airway epithelial cell from said individual, wherein activation of IGF1R is indicative that said individual is at increased risk of lung disease as compared with an individual in whom IGF1R is not activated. 
   
   
       15 . An oligonucleotide array having immobilized thereon one or more probes for one or more biomarkers of the PI3K pathway, and wherein said array does not have immobilized thereon probes for other biomarkers. 
   
   
       16 . An oligonucleotide array according to  claim 15  wherein said one or more biomarkers of the PI3K pathway are selected from the group consisting of IGF1R, PKC and combinations thereof. 
   
   
       17 . A method of reducing the risk of lung disease in an individual comprising administering to an individual at risk of lung disease one or more agents which inhibit the PI3K pathway. 
   
   
       18 . A method according to  claim 17  wherein the PI3K pathway is activated in said individual prior to administration of said one or more agents. 
   
   
       19 . A method according to  claim 17  wherein the lung disease is lung cancer. 
   
   
       20 . A method according to  claim 17  wherein said one or more agents are administered to said individual prophylactically before the development of lung disease. 
   
   
       21 . A method of differentially classifying a cytologically normal test airway epithelial cell, comprising
 identifying a gene expression signature associated with activation of a biological pathway of interest in a normal airway epithelial cell;   assessing gene expression in differentially classified airway epithelial cells to identify one or more correlations between classification of an airway epithelial cell and activation of a biological pathway of interest; and   assessing gene expression in a cytologically normal test airway epithelial cell,   wherein the gene expression profile of the cytologically normal airway epithelial cell to be classified indicates whether the biological pathway of interest is activated and thus differentially classifies the cell.   
   
   
       22 . A method according to  claim 21  wherein said biological pathway of interest is an oncogenic pathway. 
   
   
       23 . A method according to  claim 21  wherein said differential classification is increased risk of disease versus decreased risk of disease. 
   
   
       24 . A method according to  claim 21  wherein said differential classification is response to treatment versus non-response to treatment.