Lung cancer is the leading cause of cancer related death in the United States. Gene expression profiles in non-small cell lung cancer (NSCLC) reflect unique aspects of individual tumors and provide precise prognostic information. In previously published studies, using gene signatures reflective of deregulated oncogenic signaling pathways and corresponding tumor microenvironment, we have been able to identify the state of critical regulatory events within an individual tumor, in patients with solid tumors. This proposal aims to build upon a strategy that makes use of gene expression signatures that define the deregulation of various oncogenic pathways with specific relevance to NSCLC. The goal of this work is to develop a genomicbased integrated approach to the challenge of personalized targeted strategies in patients with NSCLC - by dissecting tissue specific differences in the Src pathway, and further by validating and refining a molecular signature of Src pathway activation. We believe that such an approach will allow us to truly characterize lung tumors for the status of the SRC pathway and then match therapeutics based pathway status - a rationale approach to the goal of delivering individualized therapy to a given patient with lung cancer. During the study period, we propose to complete the following: (i) Develop a genomic signature representative of Src pathway activity specific to lung epithelium and study relevant sub pathways using Bayesian factor regression modeling, (ii) Validate and refine the performance characteristics of the Src signature using cell lines and patients samples. Such a strategy will add to the validity of a genomic approach to targeting patients with novel treatment strategies;systematic steps that are critical before the implementation of such strategies in large phase III trials using Src targeted therapies.
The development of gene expression profiles as predictive measures of outcome has the potential to vastly improve our understanding of cancer biology and outcomes. Equally important are the goals of this study which are to build upon a strategy that makes use of gene expression patterns to develop profiles that define the deregulation of oncogenic pathways in non-small cell lung cancer (NSCLC), in particular the SRC pathway. Such a strategy may enable us to select the most appropriate chemotherapy for the individual patient offers the potential to increase efficiency of therapy and to identify new therapeutic opportunities for patients with NSCLC - a disease in which there are limited targeted therapeutic opportunities. In the RO1 proposal, to achieve the goal of developing novel strategies for the treatment of patients with NSCLC, we propose to develop a expression-based signature of Src pathway activity specific to lung cancer, using human bronchial epithelial cells and extend the molecular understanding of the Src pathway (Aim 1). In addition, we will utilize lung cancer cell lines and human samples treated with a Src inhibitor as validation. Thus, in a proof of concept manner, validating the utility of a genomic approach and creating future opportunities for novel therapies based on the pathway status in patients with NSCLC.
