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Phouthone Keohavong - Research

Research Interests

My group's research interests are to elucidate the cellular and molecular mechanisms by which environmental carcinogens cause lung cancer and to identify markers for the diagnosis, prognosis and treatment of this disease. We investigate genetic and epigenetic changes in oncogenes and tumor suppressor genes in specimens obtained from lung cancer patients and individuals at high risk for developing lung cancer. In addition, we apply new mouse models to investigate tobacco smoke carcinogen-mediated lung tumorigenesis. We would like to understand how airway epithelial cells are involved in the initiation and progression of lung tumors, and how they are influenced by environmental factors that increase lung cancer risk and how they respond to therapies.

1. Exposure to environmental chemicals is widely accepted as a cause of increased risk of human cancer. This observation stems from the ability of many environmental chemicals to cause damage and consequent mutations in genomic DNA. My research focuses on understanding the molecular mechanisms of mutagenesis and the mutational pathways that link environmental chemicals to cancer. We have developed and applied new molecular approaches to determine the mutational spectra for potential carcinogens. Thus, our studies include identification of the types, positions, and frequencies of mutations after treatment with the chemical agent. We are utilizing both in vitro and in vivo approaches in our efforts to elucidate the steps between exposure to a harmful environmental agent and DNA alterations in certain key genes, the process that culminates in unchecked cellular growth.
   
   
2. The in vitro studies subject various human cell lines to treatment with suspected carcinogens, followed by assays for DNA adducts and mutations. The mutational spectra so determined provide useful fingerprints of the chemicals investigated. Similar studies are performed on specimens taken from cancer patients and at-risk individuals. In these in vivo studies we are particularly interested in the mutational spectra found in oncogenes, tumor suppressor genes, and in certain selectable genes. Comparison of the mutational spectra observed in vivo with those established in vitro will aid in the understanding of whether: (a) mutations in selectable genes resemble those observed in various oncogenes and tumor suppressor genes, (b) a correlation exists between an established mutational spectrum and exposure to a suspected carcinogen, and, (c) alterations of the genes investigated provide useful markers for early cancer detection. In summary, our work will have an impact on the diagnoses, prognoses and therapies relevant to environmentally based cancer.
   
   
3. Another significant research interest involves lung cancer, as this disease is the leading cause of cancer mortality in the United States and other industrialized countries - in spite of improved therapy for many cancers and a nationwide anti-smoking campaign. The development of lung cancer follows a long latent period as the normal respiratory epithelium is exposed to the carcinogens in tobacco smoke. The response of normal cells to these stresses is believed to be a predictable progression starting with high-grade dysplasia, progressing to carcinoma in situ, and culminating in invasive cancer. One of our research projects has focused on applying new molecular methods to sample cells from the histopathologically different areas of lung tissues obtained from various stages of tumor development. The aim is to identify gene(s) that are implicated in an early stage of lung cancer development. Analysis of alterations in such gene(s) in specimens, including blood and sputum samples obtained from patients at risk for lung cancer (such as heavy smokers and COPD patients) may provide useful biomarkers for early detection of lung cancer.