The applicant seeks to become an outstanding surgeon-scientist. This proposal describes a 5 year training program that will provide didactic teaching, acquisition of new methods, interactions with other scientists, career guidance, and supervised research to develop him into a superb investigator. He has performed high-quality research at the University of Pittsburgh under the mentorship of Timothy R. Billiar and Walter Storkus for the last three years. To develop his research career, he seeks more time commitment to basic research which would be made possible by the K08 award. The program will promote the command of two disciplines, apoptosis/cell cycle regulation and tumor immunology. Dr. Billiar is a recognized leader in apoptosis studies, and Dr. Storkus is a recognized leader in tumor immunology. The applicant's research has strong links to both. Research will focus on the role of IRF-1 in tumor suppression of breast cancer in vitro and in vivo. In preliminary research recombinant adenovirus for IRF-1 (Ad-IRF-1) has been constructed and confirmed to have functional expression in mouse and human breast cells. Ad-IRF-1 has been found to inhibit the growth of breast cancer cells, but not non-malignant breast cells, and tumor suppression of breast cancer has been found in vitro and in vivo. The antitumor effect seems to be mediated by apoptotic, cell cycle, and immune factors. Using Ad-IRF-1 and in vitro and in vivo models the role of IRF-1 in breast cancer specific growth inhibition and enhanced tumor immunogenicity will be evaluated.
The specific aims i nclude: 1) Determine the direct role of apoptosis and cell cycle effects in IRF-1 induced cancer-specific growth inhibition in vitro and in vivo, 2) Evaluate the enhanced immunogenicity of tumor cells infected with Ad-IRF-1 in prophylactic and therapeutic murine tumor models, and 3) Determine the role of IRF-1 induced apoptosis in the breast cancer immune response. This research combines the strengths of the mentors, and defines the antitumor mechanism of apoptosis and tumor immunogenicity and the interaction between them in breast Ca by IRF-1.
