Our goal is to understand the molecular pathogenesis of common human cancers such as lung and breast cancer and use this information for diagnosis, prevention, and treatment of these diseases. These studies also provide an opportunity to dissect biochemical pathways of cell regulation, growth, and differentiation. Human cancers arise because of mutations or epigenetic changes (>20 per clinically evident tumor) in dominant and recessive oncogenes (tumor suppressor genes), and we wish to identify all of the genes commonly deregulated by these mechanisms in human lung and breast cancer. We are approaching this by study candidate genes, systematic molecular dissection of biochemical pathways, and global approaches such as microarray analysis of gene expression in human cancer cells. A major advance in this area has been our development of new immortalized lung epithelial cells that can be genetically manipulated with oncogenic changes to study the individual steps in lung cancer pathogenesis. We also study selectively altering the expression of oncogenes and tumor suppressor genes in human lung and breast cancer cell lines to determine the importance of each gene in the pathogenetic process and also whether they represent new targets for therapy. New discoveries in DNA methylation (with epigenetic inactivation of gene expression) and difference in expression of microRNAs (miRNAs) also identify these as important mechanisms. We have developed new genome wide approaches to identify genes regulated by epigenetic mechanisms as well as the reversal of this process with new small molecules in human cancer. Likewise, we have collaboratively worked to identify changes in miRNA expression in tumors that correlate with relevant biologic properties such as chemotherapy response. Recent advances in the identification of a small subset ((<1% of the cells) of cells in human tumors with stem cell like properties (cancer stem cells) have indicated the importance of this subset in tumor maintenance, metastases, and drug resistance and we are working on ways to identify lung cancer stem cells. Lung and breast cancer also differ in their genome wide mRNA and protein expression profiles and these differences can provide information on tumor classification, prognosis, and potentially response to specific therapies. We are particularly interested in developing profiles that predict ahead of time for each individual patient which drugs that patient?s tumor will respond to best. This includes how to combine drugs in the treatment of individual patients. As part of this we are studying the expression of nuclear hormone receptors and using this information to develop new ways to hormonally manipulate tumors. The lung cancer work is done as part of a NCI Special Program of Research Excellence (SPORE) Grant. Finally, we are collaborating with Radiation Oncology to study the effect of low dose gamma rays and high energy particle (HZE particle) radiation on the pathogenesis of lung cancer and regular radiation on the response of lung cancer to radiation therapy. These studies are done as part of a NASA Center of Research Excellence (NSCOR) grant. Understanding the functions of the genes mutated, the pathways disrupted, and gene and protein expression signatures will provide a foundation for a translational (bench to bedside) research approach to human cancer and also help us understand fundamental aspects of cell regulation.
RECENT PUBLICATIONS
Das, A. K., Sato, M., Story, M. D., Peyton, M., Graves, R., Redpath, S., Girard, L., Gazdar, A. F., Shay, J. W., Minna, J. D., and Nirodi, C. S., "Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation." Cancer Res, 66:9601-9608, 2006
Deng, W. G., Kawashima, H., Wu, G., Jayachandran, G., Xu, K., Minna, J. D., Roth, J. A., and Ji, L., "Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer ce" Cancer Res, 67:709-717, 2007
Sato, M., Shames, D. S., Gazdar, A. F., and Minna, J. D, "A Translational View of the Molecular Pathogenesis of Lung Cancer." J Thorac Oncol, 2:327-343, 2007
Zhou, B. B., Peyton, M., He, B., Liu, C., Girard, L., Caudler, E., Lo, Y., Baribaud, F., Mikami, I., Reguart, N., Yang, G., Li, Y., Yao, W., Vaddi, K., Gazdar, A. F., Friedman, S. M., Jablons, D. M., Newton, R. C., Fridman, J. S., Minna, J. D., and Scherle, P. A., "Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer." Cancer Cell, 10:39-50, 2006
SIGNIFICANT PUBLICATIONS
Das, A. K., Chen, B. P., Story, M. D., Sato, M., Minna, J. D., Chen, D. J., and Nirodi, C. S., "Somatic Mutations in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor (EGFR) Abrogate EGFR-Mediated Radioprotection in Non-Small Cell Lung Carcinoma." Cancer Res, 67:5267-5274, 2007
Lam, D. C., Girard, L., Ramirez, R., Chau, W. S., Suen, W. S., Sheridan, S., Tin, V. P., Chung, L. P., Wong, M. P., Shay, J. W., Gazdar, A. F., Lam, W. K., and Minna, J. D., "Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non-Small-Cell Lung Cancer Reveals Differences between Smokers and Nonsmokers." Cancer Res, 67:4638-4647, 2007
Sato, M., Vaughan, M. B., Girard, L., Peyton, M., Lee, W., Shames, D. S., Ramirez, R. D., Sunaga, N., Gazdar, A. F., Shay, J. W., and Minna, J. D., "Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells." Cancer Res, 66:2116-2128, 2006
Shames, D. S., Girard, L., Gao, B., Sato, M., Lewis, C. M., Shivapurkar, N., Jiang, A., Perou, C. M., Kim, Y. H., Pollack, J. R., Fong, K. M., Lam, C. L., Wong, M., Shyr, Y., Nanda, R., Olopade, O. I., Gerald, W., Euhus, D. M., Shay, J. W., Gazdar, A. F., and Minna, J. D., "A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies." PLoS Medicine, 3:e486, 2006
Whitehurst, A. W., Bodemann, B. O., Cardenas, J., Ferguson, D., Girard, L., Peyton, M., Minna, J. D., Michnoff, C., Hao, W., Roth, M. G., Xie, X. J., and White, M. A., ". Synthetic lethal screen identification of chemosensitizer loci in cancer cells." Nature, 446:815-819, 2007
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