"Clinical Protocol Modification of Oncogene and Tumor Suppressor 
Gene Expression in Non-Small Cell Lung Cancer (NSCLC)" 
1.0 OBJECTIVES 
The objective of this protocol is to evaluate the toxicity and possible therapeutic 
efficacy of the intralesional administration of retroviral constructs containing antisense 
(AS) K-ras (for tumors with mutated K-ras) and wildtype p53 (wtp53) (for tumors with 
mutated or deleted p53) into residual endobronchial NSCLC which obstructs a 
bronchus and which is refractory to conventional therapy. 
2.0 BACKGROUND AND RATIONALE 
2.1 Molecular events in NSCLC 
Lung cancer remains the leading cause of cancer deaths in the United States 
where it kills more than 140,000 people annually. Recently, age-adjusted 
mortality from lung cancer has surpassed that from breast cancer in women. 
Although implementation of smoking-reduction programs has decreased the 
prevalence of smoking, lung cancer mortality rates will remain high well into the 
21st century 1 . Unfortunately, all current treatment modalities, including radiation 
therapy, surgery, and chemotherapy, have limited effectiveness. The rational 
development of new therapies for lung cancer will depend on an understanding 
of the biology of lung cancer at the molecular level. Research in our laboratory 
has identified critical molecular events leading to NSCLC development and 
progression. The goal of this research is to directly modify the cancer cell to 
eliminate the expression of gene products which are responsible for the 
maintenance, or progression of the malignant phenotype or to restore in normal 
form deleted or mutated gene products that suppress the characteristics of the 
malignant phenotype. 
The purpose of this protocol is to investigate molecular mechanisms that may 
influence the growth and progression of human lung cancer; our goal is 
development of therapeutic agents specifically targeted at the molecular level. 
The most common lung cancer histologies (80%) are grouped under the term 
non-small-cell lung cancer (NSCLC) and include squamous, adenocarcinoma, 
and large-cell undifferentiated. Many of the current data on the molecular 
biology of lung cancer come from the study of the more uncommon small-cell 
lung cancer (SCLC). SCLC can be distinguished from NSCLC by the 
neuroendocrine features of the cells; SCLC is very responsive to chemotherapy 
but recurs rapidly after treatment. NSCLC also may serve as a model for other 
carcinogen-induced malignancies. The approaches and observations 
developed in this study may be applicable to other types of epithelial cancers. 
Abundant evidence has accumulated that the process of malignant 
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