Breast cancer is one of the major causes of death for women in the United States. Overexpression of the c-erb B2 oncogene was reported to correlate positively with poor survival for breast and ovarian cancer patients. It is also known that c-erb B2 overexpression can enhance metastatic potential of human cancer cells and induce resistance to chemotherapeutic agents. Therefore, c-erb B2 oncogene is an excellent target for novel anti-cancer agents for c-erb B2 overexpressing cancer cells. The applicant and coworkers have previously shown that the adenoviral E1A gene functions as a tumor suppressor for the c-erb B2-overexpressing cancer cells through repression of c-erb B2 transcription. During the previous period of support, the applicant demonstrated that with the appropriate delivery system such as cationic liposome or adenovirus vectors, E1A can suppress tumor formation and prolong survival time in tumor-bearing mice. Based on these results, an investigation new drug (IND) was filed at the FDA and phase I gene therapy trials were approved by the FDA and NIH Recombinant DNA Advisory Committee (RAC). Phase I trial entitled, """"""""Phase I Study of E1A Gene Therapy for Patients with Metastatic Breast or Ovarian Cancer That Overexpress c-erb B2"""""""" has recently been initiated at the applicant's institution. This competing renewal application will further investigate the E1A tumor suppression function by modification of the E1A gene to enhance tumor suppression function and reduce potential side effects (if any), development of a specific expression vector to express E1A only in the target breast cancer cells and examination of the hypothesis that E1A, through repression of c-erb B2 can sensitize response of breast cancer cells to chemotherapeutic drugs. The outcomes from this application will lay scientific foundation and are critical for the design of phase II and phase III clinical trials in the future. The long-term goal of this application is to develop novel therapeutic approaches for patients with breast cancer.
The specific aims of this application are: (1) improvement of tumor suppression activity of E1A in c-erb B2-overexpressing breast cancer cells, (2) localization of the functional region of the E1A gene that can inhibit c-erb B2 overexpression and c-erb B2-induced malignancy, (3) to test potential synergistic effects of E1A gene therapy in chemotherapy for breast cancer cells with enhanced c-erb B2 expression and (4) the development of vectors for preferential expression of E1A and c-erb B2-overexpressing breast cancer cells.
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