Receptor tyrosine kinases (RTKs) have been shown to be important as therapeutic targets against lung cancer. However, even with the RTK epidermal growth factor receptor inhibition, the response with small molecule inhibitors is at best 5%-15% in refractory advanced NSCLC. We have recently identified that c-Met is overexpressed in NSCLC and NSCLC and may potentially serve as an important therapeutic target in lung cancer. C-Met is a RTK important in cell proliferation, motility, invasion, metastasis, angiogenesis, wound healing, and tissue regeneration. The ligand for c-Met is the hepatocyte growth factor (HGF). Utilizing immunohistochemical analysis, we show that 69% of adenocarcinoma tissue samples, 71% of squamous cell carcinoma samples, and 78% of large cell carcinomas have c-Met overexpression as compared to adjacent normal tissues. In some of the NSCLC tumor tissue samples, we also show activation of c-Met (in the juxtamembrane domain at pY1003 and autophosphorylation sites at pY1230/1234/1235). As preliminary data, we have analyzed the c-Met gene in 127 lung adenocarcinoma tumor tissue samples and have identified unique mutations in the regulatory juxtamembrane domain and the semaphorin domain (at the Nterminus of c-Met). Interestingly, we did not find any mutations in the tyrosine kinase domain of c- Met. We have also been able to obtain small molecule inhibitors and inhibitory antibodies against c- Met and show specific growth inhibition in NSCLC cell lines and in vivo mouse xenograft models. Our hypothesis is that c-Met is an important therapeutic target in NSCLC. We will determine the specific role of c-Met and therapeutic targeting of c-Met in NSCLC via these specific aims: 1. Determine the role of c-Met/HGF axis and mutations of c-Met in biological and biochemical functions of non-small cell lung cancer cells;2. Determine the in vitro and in vivo effects of inhibiting c-Met in NSCLC;3. Determine the effects of c-Met/HGF signaling and inhibition on PI3K/AKT/mTOR pathway in NSCLC;4. Conduct an anti-c-Met phase I/I I clinical trial against NSCLC. Through the achievement of the goals proposed in these specific aims, we will arrive at novel therapy against c- Met in lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125541-04
Application #
7742242
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2007-01-15
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$262,485
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
West, Allison H; Yamada, S Diane; MacMahon, Heber et al. (2014) Unique metastases of ALK mutated lung cancer activated to the adnexa of the uterus. Case Rep Clin Pathol 1:151-154
Diamond, Jennifer R; Salgia, Ravi; Varella-Garcia, Marileila et al. (2013) Initial clinical sensitivity and acquired resistance to MET inhibition in MET-mutated papillary renal cell carcinoma. J Clin Oncol 31:e254-8
Sadiq, Ahad A; Salgia, Ravi (2013) MET as a possible target for non-small-cell lung cancer. J Clin Oncol 31:1089-96
Lukas, Rimas V; Vigneswaran, Janani; Salgia, Ravi (2013) Etoposide and temozolomide in combination for the treatment of progressive small-cell lung cancer central nervous system metastases: two cases. Tumori 99:e73-6
Morales La Madrid, Andres; La Madrid, Andres Morales; Campbell, Nicholas et al. (2012) Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin's lymphoma, and neuroblastoma. Target Oncol 7:199-210
Rehman, Jalees; Zhang, Hannah J; Toth, Peter T et al. (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 26:2175-86
Lo, Fang-Yi; Chang, Jer-Wei; Chang, I-Shou et al. (2012) The database of chromosome imbalance regions and genes resided in lung cancer from Asian and Caucasian identified by array-comparative genomic hybridization. BMC Cancer 12:235
Sadiq, Ahad A; Salgia, Ravi (2012) Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor. J Thorac Oncol 7:S372-4
Lo, Fang-Yi; Tan, Yi-Hung Carol; Cheng, Hung-Chi et al. (2011) An E3 ubiquitin ligase: c-Cbl: a new therapeutic target of lung cancer. Cancer 117:5344-50
Nwizu, Tobenna; Kanteti, Rajani; Kawada, Ichiro et al. (2011) Crizotinib (PF02341066) as a ALK /MET inhibitor- Special Emphasis as a Therapeutic Drug Against Lung Cancer. Drugs Future 36:91-99

Showing the most recent 10 out of 57 publications