ADENOVIRUS E1A AS A THERAPEUTIC AGENT IN BREAST CANCER

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DESCRIPTION (Applicant's Description): Career Goal: The applicant's career goal is to become an established physician-scientist at an academic institution in a field of therapy that relates to the use of molecular biology techniques in medical oncology. He especially hopes that he can be involved in translational breast cancer research related to dose-intensive chemotherapy with blood and marrow transplantation support. He firmly believes that understanding the molecular mechanisms of breast cancer will result in improved long-term, disease-free survival rate among patients with advanced breast cancer. To achieve this goal, he has enrolled in a Ph.D. program at The University of Texas Graduate School of Biomedical Sciences under the supervision of Mien Chie Hung, Ph.D. and is providing patient care as a staff member in the Department of Blood and Marrow Transplantation at The University of Texas M. D. Anderson Cancer Center. Proposal: Breast cancer is one of the most common causes of cancer mortality for women in the United States. The major cause of treatment failure in patients with breast cancer after dose-intensive chemotherapy still remains disease relapse, presumably due to the chemoresistance of residual breast cancer cells. Overexpression of the HER-2/neu oncogene occurs in 30% of breast cancers and has been associated with poor prognosis. This may be due to the fact that HER-2/neu induces resistance to chemotherapeutic agents. The adenovirus type 5 E1A gene product is known to repress HER-2/neu expression at a transcription level. The sponsor's laboratory has previously shown that HER-2/neu expression can be repressed in HER-2/neu overexpressing breast cancer cell lines using adenoviral vector or cationic liposome as a delivery system for the E1A gene. Recently, it has been reported that E1A s u ppresses tumorigenicity by a variety of mechanisms in addition to transcriptional repression of HER-2/neu. The applicants are currently conducting a phase I clinical trial of E1A gene therapy for patients with HER-2/neu-overexpressing breast cancer. Therefore, the ultimate goal of this proposal is to expand and establish the anti-oncogenic activity of the E1A gene against human breast cancer by combining it with chemotherapeutic agents or the p53 gene, and to elucidate their cytotoxic mechanism. The proposed experiments are aimed at translating the findings from basic research into clinically useful therapeutic agents. They hope that this novel approach will be applied to the phase II study of E1A gene therapy and improve the efficacy and the long-term outcome of dose-intensive chemotherapy with blood and marrow transplantation in breast cancer by combining them with E1A gene therapy.