In the previous grant period, we demonstrated proof of principle that the Hepatocyte Growth Factor (HGF)/c-Met signaling pathway is an important mediator of growth of human non-small cell lung tumors and an independent negative prognostic indicator of poor survival for lung adenocarcinoma patients. We produced three novel inhibitors of the c-Met pathway (an antisense c-Met vector, a competitive inhibitor of HGF, and siRNA to HGF) and also produced a transgenic mouse that overexpresses the HGF gene in the airways and shows enhanced susceptibility to lung carcinogenesis induced by an important tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These results support the validity of targeting the HGF/cMet pathway for therapy and/or prevention of lung cancer. In the proposed second funding period, we will build on those observations with two major goals: understanding more about the mechanism by which the HGF/c-Met pathway increases non-small cell lung cancer (NSCLC) tumor formation and promotes lung tumor growth and progression, and utilizing information about the mechanistic pathways to develop and test anti-tumor agents in preclinical models of human lung cancer. This work will form the rationale for future use of HGF/c-Met-targeted anti-tumor agents in clinical trials. The hypothesis we will test in the next grant period is three-fold (1) The HGF/c-Met pathway activates the enzyme cyclooxygenase 2 (COX-2) via the MAP kinase pathway (and possibly other pathways) in non-small cell lung cancer (NSCLC), resulting in upregulation of important growth-promoting pathways that are controlled by prostaglandins; (2) targeting the HGF/c-Met pathway and the COX-2 pathway alone or together will result in a pronounced reduction in established NSCLC tumor xenograft growth and (3) targeting these pathways also or together will also inhibit or prevent tobacco carcinogen-induced lung tumorigenesis in a transgenic HGF animal model.
Three specific aims are proposed to test these hypotheses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079882-08
Application #
7109179
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Snyderwine, Elizabeth G
Project Start
1999-08-12
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
8
Fiscal Year
2006
Total Cost
$293,645
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Stabile, Laura P; Rothstein, Mary E; Gubish, Christopher T et al. (2014) Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF. J Thorac Oncol 9:1285-93
Dulak, A M; Gubish, C T; Stabile, L P et al. (2011) HGF-independent potentiation of EGFR action by c-Met. Oncogene 30:3625-35
Stabile, Laura P; Rothstein, Mary E; Keohavong, Phouthone et al. (2010) Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice. Cancers (Basel) 2:2153-2170
Stabile, Laura P; Rothstein, Mary E; Keohavong, Phouthone et al. (2008) Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis. Mol Cancer Ther 7:1913-22
Siegfried, Jill M; Gubish, Christopher T; Rothstein, Mary E et al. (2007) Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non small-cell lung cancer. Mol Pharmacol 72:769-79
Stabile, L P; Lyker, J S; Huang, L et al. (2004) Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther 11:325-35
Siegfried, Jill M; Luketich, James D; Stabile, Laura P et al. (2004) Elevated hepatocyte growth factor level correlates with poor outcome in early-stage and late-stage adenocarcinoma of the lung. Chest 125:116S-9S
Lui, Vivian Wai Yan; Thomas, Sufi Mary; Zhang, Qing et al. (2003) Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene 22:6183-93
Stabile, Laura P; Davis, Autumn L Gaither; Gubish, Christopher T et al. (2002) Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 62:2141-50
Siegfried, J M (2001) Women and lung cancer: does oestrogen play a role? Lancet Oncol 2:506-13