Cigarette smoking is causally associated with development of cancer of the lung, head & neck region, esophagus, bladder, and other sites by overwhelming epidemiological and biologic evidence. Cessation of smoking results in a slow decline in risk of cancer development that remains elevated compared to never smokers beyond 15 years after smoking cessation. Thus, strategies to reduce the impact of lung cancer in former smokers are needed. The epidermal growth factor receptor (EGFR) and cyclo-oxygenase II (COX-2) have been implicated in the development and maintenance of lung cancer. Clinical trials of the EGFR tyrosine kinase inhibitor, ZD1839, in patients with established cancer have demonstrated biological and anti-tumor effects. In the first part of this application, a Phase I, open-label, dose escalation clinical trial will be conducted to determine the maximal tolerable dose of ZD1839, and the associated effect on EGFR signaling, when used as a chemopreventive agent in former smokers. Former smokers treated with curative intent for early stage lung or head and neck cancer will be treated in cohorts of escalating doses of ZD1839. Measures of drug effect (EGFR, c-fos, apoptosis) and biomarkers of lung cancer risk will be measured in bronchial epithelium before and after taking drug for 12 weeks. Potential efficacy of EGFR and/or COX-2 inhibition (using ZD1839 and Celecoxib, respectively) will then be assessed in a Phase II, placebo-controlled, clinical trial assessing effect on bronchial epithelial genetic loss and other surrogate biomarkers of lung cancer risk.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA096123-05
Application #
7124762
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (J3))
Program Officer
Szabo, Eva
Project Start
2002-09-26
Project End
2007-08-31
Budget Start
2006-09-25
Budget End
2007-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$442,543
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kim, Seok Jin; Rabbani, Zahid N; Dong, Fan et al. (2010) Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer. Med Oncol 27:91-7
Riedel, Richard F; Wang, Xiaofei; McCormack, Meg et al. (2006) Impact of a multidisciplinary thoracic oncology clinic on the timeliness of care. J Thorac Oncol 1:692-6
Riedel, Richard F; Crawford, Jeffrey; Dunphy, Frank et al. (2006) Phase II study of carboplatin, irinotecan, and thalidomide combination in patients with extensive stage small-cell lung cancer. Lung Cancer 54:431-2
Dong, Fan; Li, Sufeng; Pujol-Moix, Nuria et al. (2005) Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol 130:620-7
Kim, Seok Jin; Rabbani, Zahid N; Dewhirst, Mark W et al. (2005) Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49:325-35
Kim, Seok Jin; Rabbani, Zahid N; Vollmer, Robin T et al. (2004) Carbonic anhydrase IX in early-stage non-small cell lung cancer. Clin Cancer Res 10:7925-33