The adenovirus type 5 E1A is associated with multiple anti-tumor activities including the downregulation of the overexpressed HER-2, the repression of metastasis-promoting activities, the enhancement of sensitivity of cancer cells to genotoxic agents (apoptosis inducers), and etc. Our previous studies using E1A gene coupled with cationic liposome had shown that it was an effective gene therapy approach to treat cancer in orthotopic animal models. Based on thrse achievements, multiple clinical trials using E1A/liposome were approved to target solid tumors of the breast, ovary, and head and neck via intrathoracic, intraperitoneal, and intratumor injections, respectively. We were able to show in the Phase I trial that these E1A/liposome treatments, when treated locally and at safe dosage, could result in downregulation of HER-2 and sensitization to apoptosis in tumor cells of the treated patients. Although the phase I trial data is encouraging and has proved the concept that E1A gene therapy is able to sensitize tumor cell death in humans, the E1A/liposome complex was administrated locally to the thoracic cavity via catheters in breast cancer patients. However, metastatic breast cancer is a systemic disease, and systemic delivery of a therapeutic agent is required to achieve effective therapy. Therefore, it is critical to develop systemic delivery systems of E1A gene therapy for metastatic breast cancer patients. We have recently used a newly developed non-viral systemic delivery system, LPD, and demonstrated suppressed tumor growth in an orthotopic breast cancer animal model through a systemic delivery of E1A gene by intravenously injection. In this proposal, we will continue our investigation on the therapeutic effects of the E1A/LPD gene therapy in the breast animal model through systemic delivery. We also propose a clinical trial using this system to test the therapeutic efficacy in breast cancer patients. In addition, we will continue our study to further elucidate the molecular mechanisms underlying the E1A-mediated sensitization to Taxol- and TNF-alpha-induced apoptosis in breast cancer cells and that will provide a scientific basis for us to develop combined therapy using E1A gene and Taxol (or TNF-alpha). The long-term goal of this proposal is to translate our previous laboratory discovery of E1A gene as a tumor suppressor gene into an effective therapeutic agent for breast cancer patients in clinic.
The Specific Aims of this proposal are: 1. To investigate the E1A-mediated sensitization to Taxol-induced apoptosis in breast cancer cells. 2. To investigate the E1A-mediated sensitization to TNF-alpha-induced apoptosis in breast cancer cells. 3. To develop a tumor specific promoter using hTERT promoter-driven E1A for breast cancer gene therapy. 4. To develop E1A clinical trials for metastatic cancer patients.
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