Bik (Bcl2 interacting killer) is a pro-apoptotic gene that contains only one of the Bcl-2 homology regions, the BH3 domain, and has recently been recognized as an essential initiator of apoptosis. We have demonstrated that the Bik gene complexed with a non-viral gene delivery system when given intravenously, significantly inhibited the growth and metastasis of human breast cancer cells implanted in nude mice and prolonged the life span of the treated animals. In addition, we developed a Bik mutant, BikDD in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, and found the mutant's anti-cancer activity more potent than wild type's. These results suggest that BikDD may serve as a potent therapeutic gene for breast cancer in a gene therapy setting. To develop effective gene therapy approaches to treat metastatic breast cancer, we have also recently developed a modified Topoisomerase lla promoter, CT90 which can express the gene of interest preferentially in breast cancer cells over the normal cells/tissues. A CT90-driven BikDD construct, CT90-B kDD will be more specific to suppress breast cancer cell growth and may have minimal toxicity compared with a non-specific promoter such as the cytomegalovirus (CMV) promoter. The long-term goal of this proposal is to develop an effective therapeutic approach to treat breast cancer. To achieve this goal, four SPECIFIC AIMS are proposed:
SPECIFIC AIM 1 : Determination of Anti-tumor activity of BikDD/liposome via non-invasive imaging systems in mammary tumor-bearing animal models;
SPECIFIC AIM 2 : Development of a targeting gene therapy for breast cancer;
SPECIFIC AIM 3 : Development of a combination therapy with BikDD/liposome and chemotherapy;
and SPECIFIC AIM 4 : Development of a phase I clinical trial using BikDD/liposome formulation. Sucess of this proposal will warrant further clinical trials to develop an effective therapeutic approach to treat metastatic breast cancer.
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