Research: Our research group is focused on investigating the genetic basis for human lung cancer and to develop new strategies for clinical trials. We have recently identified the genetic basis for pulmonary mucoepidermoid carcinoma by isolating and cloning the chromosomal breakpoint of a characteristic t(11;19) translocation. To date we have cloned the two novel genes that form a mutant gene fusion protein in these tumors and have shown that they can function to deregulate the Notch pathway and to transform epithelial cells in culture. We have also identified the same translocation event in multiple other tumors arising from major and minor salivary glands. Future work will define the role of this new molecular target and to explore possible clinical applications. This project was part of an effort to study the genetic basis of lung cancer in younger patients and we will continue to identify and collect samples from the clinic at the National Naval Medical Center. In addition, we have studied the role of the RB tumor suppressor pathway in human cancer and have demonstrated that the RB/p16 tumor suppressor pathway is inactivated in 100% of small cell lung cancer (SCLC) and non-SCLC. We are currently studying the interrelationships between RB/p16 and the cyclin d/ras pathways. We are also continuing a long-standing project on the functional properties of the RB tumor suppressor protein using mutant alleles isolated from patients with lung cancer and from families linked with the phenoytpe of incomplete penetrance. We have also identified caspase-mediated cleavage of the C-terminal 42 amino acids of RB at the onset of apoptosis and we have now developed a mouse model to study the functional consequences of this cleavaage event during normal development and during apoptosis.
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