Research Projects
Our group’s research interest is in the area of chemoprevention and genetics of lung cancer, including three major projects: 1) lung cancer chemoprevention studies in rodent models with the goals of identifying new effective agents and elucidation of their mechanisms of action; 2) identification of human and mouse lung cancer susceptibility gene(s); and 3) functional analysis of lung cancer genes using transgenic mice. Lung cancer is the leading cause of death in men and women in the United States. Although the relative risk of developing lung cancer declines in smokers who quit, former smokers remain at high risk for at least five years. Given that smoking cessation is a major public health initiative, former smokers will increasingly account for a high percentage of lung cancer. A potential important approach to reduce the large number of tobacco caused cancer deaths is chemoprevention. The long-term goal of You’s lab is to develop chemopreventive strategies to reduce the incidence of lung cancer in high-risk current and former smokers. Our group specifically focuses on farnesyltransferase inhibitors (FTI), anti-tumor B, budesonide (a glucocorticoid agonist), green tea extracts (Polyphenon E), myo-inositol, and difluoromethylomithine (DFMO). We are developing relationships with Washington University’s Department of Biology (Hilltop Campus), its Center for Human Nutrition, the Missouri Botanical Garden, and the Donald Danforth Plant Science Center. This group has already formed a consortium – the Botanical Program for the Prevention and Treatment of Chronic Diseases. Specifically, the Donald Danforth Plant Science Center is separating certain plant-based chemopreventive agents into their component parts for use in producing transgenic plants with high concentrations of the most active ingredients, and the Missouri Botanical Garden has plant extracts that our group will be testing for chemopreventive activity. These compounds will then be moved into clinical trials.
Additional foci of our group are identification of human and mouse lung cancer susceptibility gene(s) and functional analysis of lung cancer genes using transgenic mice. Evidence from studies of familial aggregation of lung cancer suggests that genetic factors are involved in human lung tumor development. Specifically, segregation analysis of lung cancer proband families indicates that a Mendelian co-dominant inheritance of a rare major autosomal gene is involved. This gene has been shown to account for 69%, 47%, and 22% of the cumulative incidence of lung cancer in patients at ages 50, 60, and 70, respectively. The identification of the gene(s) at this locus is currently being pursued. As a member of the Genetic Epidemiology of Lung Cancer Consortium, Dr. You’s lab is in the process of identifying familial lung cancer (FLC) pedigrees for genotyping genome-wide informative individuals in the FLC pedigrees, leading to the mapping a lung cancer susceptibility gene(s) be genetic linkage analysis of the FLC pedigrees. Synergistically to the studies in human FLC, Dr. You’s group is also conducting genetic linkage analyses of mouse lung tumor susceptibility genes using mouse models. Susceptibility to chemical induction of lung tumors in mice varies according to the strain. Genetic linkage analyses using various mouse crosses have revealed a series of pulmonary adenoma susceptibility (Pas) genes, e.g. Pas1 (chr.1), Pas2 (chr. 17), and Pas3 (chr.19), and pulmonary adenoma resistance (Par) genes, e.g. Par1 (chr.11), Par2 (chr.18), Par3 (chr.4), and Par4 (chr.12). The K-ras protooncogene is a candidate for Pas1, and the p16 gene is a candidate for Par3. These mapped loci are currently being fine-mapped using congenic mice and positional cloning. Since genetic changes found in mouse lung tumors have remarkable similarities to those seen in humans, functional analysis of several key lung cancer genes has been conducted using transgenic mouse models. For example, p53 transgenic mice with a germline missense mutation were found to have a significantly increased susceptibility to chemically induced lung tumorigenesis, making it a lung tumor model for Li-Fraumeni Syndrome in humans. Transgenic mice carrying disruptions of K-ras, p16, or BRCA1 are being used in mouse lung carcinogenesis studies to determine their involvement in lung tumorigenesis.