SPORE Project 3: E1A Gene Therapy in Ovarian Cancer
Principle Investigator: Mien-Chie Hung, Ph.D.
Ovarian cancer is one of the major causes of death for women in the United States. Overexpression 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-overexpressing cancer cells. Our experimental results indicate that adenovirus type 5, E1A, a transcriptional modulator, represses HER-2/neu transcription in HER-2/neu-overexpressing 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-overexpressing 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 Overexpresses 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 proposal is to develop E1A gene therapy as an effective therapeutic approach for ovarian cancer. The targets in this proposal are to explore other anti-tumor activities associated with E1A and to understand its mechanisms, to develop novel approaches for targeting HER-2/neu-overexpressing ovarian cancer cells and to complete phase II clinical trial using E1A/liposome treatment for HER-2 / neu-overexpressing ovarian cancer patients. The specific aims of the proposal 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-overexpressing ovarian cancer cells
- Specific Aim 4: Development of E1A gene expression system specifically targeting HER-2/neu-overexpressing ovarian cancer cells using HER-2/neu antisense iron-responsive element
- Specific Aim 5: E1A phase II clinical trials for Her-2/neu-overexpression ovarian cancer patients