The goal of this application is to develop a preclinical therapeutic model of ovarian cancer involving an adenovirus-based vector encoding the human p53 tumor suppressor gene. This application involves the introduction of a gene that has direct tumor cytotoxicity or indirect tumor growth inhibitory function (through a phenomenon termed the """"""""bystander effect""""""""), or potentially both. The applicant has demonstrated the efficacy of gene therapy in vivo using an adenovirus vector for the transfer of biologically active p53 into ovarian cancer cells. The goal of this project is to further define the following five aspects of adenovirus-based p53 gene therapy in the treatment of ovarian cancer. First, while p53 gene therapy has shown efficacy in a microscopic disease model, the applicant plans to determine whether this treatment will be effective in the presence of larger tumor volumes that more closely model human ovarian cancer. Second, because mutant p53 protein can inhibit wild type p53 function, he plans to investigate the role of specific endogenous p53 mutations on the response to adenovirus-based p53 gene therapy. These results may allow him to predict patient response to p53 gene therapy. Third, he will determine the mechanisms by which p53 acts to inhibit tumor growth in G2. It is well documented that introduction of cancer cell lines with wild-type p53 results in a G1 arrest. However, he has recently observed that certain cells arrest at the G2/M checkpoint. The arrest of cells during DNA synthesis and replication after DNA damage is thought to provide the cell with sufficient time to repair the damage before progression through the cell cycle. Fourth, because p53 has been shown to re-sensitize chemo- resistant cells to alkylating agents, he plans to determine the effectiveness of adenovirus-based p53 gene therapy alone or in combination with cisplatin therapy. Finally, some data suggest that wild-type p53 regulates a balance of potent angiogenic and anti- angiogenic factors. Thus, he plans to investigate the bystander effect of adenovirus-based p53 gene therapy on tumor angiogenesis. In this application, he intends to take the first steps toward the translation of promising preliminary data on an adenovirus-based cancer gene therapeutic model system into practical and scientifically based human trials.
| Carroll, J L; Nielsen, L L; Pruett, S B et al. (2001) The role of natural killer cells in adenovirus-mediated p53 gene therapy. Mol Cancer Ther 1:49-60 |
