Project: Research project

Project Details


DESCRIPTION (As Adapted From the Investigator's Abstract): Lung cancer arises
in a bronchial epithelium diffusely damaged by the chronic inhalation of
carcinogens in a susceptible host. The p53 gene plays an important role in the
lung carcinogenesis process. P53 gene mutations are frequently involved in the
progression of bronchial metaplasia to dysplasia. Restoration of p53 function
in dysplastic bronchial epithelium by gene transfection technologies using the
inhalation route is a logical and technically feasible strategy to prevent or
delay the progression of premalignant bronchial epithelial lesions to lung
cancer. The applicants have developed a cationic lipid/p53 gene complex (CLp53)
that is effective by regional delivery in delaying endobronchial tumor growth
in mouse models of p53-null or mutant human lung cancer. They propose to adapt
this formulation for aerosol use and to initiate clinical studies with an
optimized aerosolized CLp53 formulation (aCLp53). The hypothesis being tested
is that restoration of p53 function in the human bronchial epithelium can be
safely and effectively accomplished with the inhalation of CLp53 gene
complexes. The specific aims of the proposal are: to develop a CLp53
formulation for administration as an aerosol; optimization efforts will focus
on particle size, nebulizer type, pH, additives to enhance tissue penetration
and CL/gene complex preservation, and potential interactions with bronchial
mucus components; to study the preclinical toxicity of CLp53 by intratracheal
instillation and aerosolization in mice and rabbits; these studies are
essential for IND filing; and, to perform a Phase I clinical study of CLp53 by
aerosolization in patients with p53 mutant non-small cell lung cancer (NSCLC).
The objectives of the Phase I clinical study are: to determine the maximum
tolerated dose, optimum schedule, and dose-limiting toxicity of aCLp53; to
generate preliminary information on the ability of aCLp53 to restore p53
function in the human bronchial epithelium; and, to study the deposition and
distribution of aCLp53 in the lungs. The results of this study will provide
initial but very valuable information on the potential use of this new strategy
in the treatment of bronchial premalignancy, carcinoma in situ, and
endobronchial lung tumors.
Effective start/end date3/1/006/30/05


  • Oncology
  • Cancer Research
  • Pulmonary and Respiratory Medicine
  • Biotechnology


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