) Ovarian cancer is one of the major causes of death for women in the United States. Over-expression of the HER-2/neu oncogene was reported to correlate with poor survival for ovarian cancer patients, enhance metastatic potential of human cancer cells and induce resistance to certain chemotherapeutic agents such as taxol (paclitaxel). Therefore, HER-2/neu oncogene is an excellent target for development of novel anti-cancer agent for the HER-2/neu-over-expressing cancer cells. Our experimental results indicate that adenovirus type 5, E1A, a transcriptional modulator, represses HER-2/neu transcription in HER-2/neu-over-expressing cancer cells; and that E1A-liposome complex inhibits tumor development in an ovarian cancer animal model. We, therefore, hypothesize that E1A, through repression of HER-2/neu, may function as a tumor suppressor for HER-2/neu-over-expressing ovarian cancer cells. Based on a series of preclinical data that derives this hypothesis, a phase I clinical trial entitled """"""""Phase I Study of E1A Gene Therapy for Patients with Metastatic Breast or Epithelial Ovarian Cancer that Over-expresses HER-2/neu"""""""" has recently been completed. The results are encouraging and suggest feasibility of the E1A gene therapy for further clinical trials. The long-term goal of this proposed project is to develop E1A gene therapy as an effective therapeutic approach for ovarian cancer. The targets in this proposed project are to explore other anti-tumor activities associated with E1A and to understand its mechanisms, to develop novel approaches for targeting HER-2/neu-over-expressing ovarian cancer cells, and to complete phase II clinical trial using E1A/liposome treatment for HER-2/neu-over- expressing ovarian cancer patients.
The specific aims of the proposed project are described as following:
Specific Aim 1 : E1A tumor suppressor function in ovarian cancer cells.
Specific Aim 2 : Mechanism of E1A tumor suppression function in ovarian cancer cells.
Specific Aim 3 : E1A-mediated chemo-sensitization in HER-2/neu-over- expressing ovarian cancer cells.
Specific Aim 4 : Development of E1A gene expression system specifically targeting HER-2/neu-over- expressing ovarian cancer cells using HER-2/neu antisense iron-responsive element.
Specific Aim 5 : E1A phase II clinical trials for HER-2/neu-over-expression ovarian cancer patients.
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