) New treatments for ovarian cancer are clearly needed. One novel approach under active preclinical and clinical evaluation is gene therapy. Strategies being investigated include use of replication incompetent retroviruses or adenoviruses (AD) to deliver suicide genes such as herpes simplex virus (HSV) thymidine kinase (tk) to activate ganciclovir (GCV) into a cytotoxic drug. One major limitation discovered in an ongoing phase I trial for malignant mesothelioma at the University of Pennsylvania is poor depth of penetration of ADHSV tk into the tumor after intracavitary delivery. A promising approach to overcome this problem is to use replication-competent adenoviruses. When such viruses infect cells and replicate, it causes cell lysis. In addition, active virus is released to infect other tumor cells. By coupling this mechanism of enhanced killing and infection with the ability to activate GCV, we hypothesize that anti-tumor efficacy will be enhanced. However, the delivery of such replication competent viruses causes some safety concerns. To address this issue, a virus conditionally replicative in tumor cells will be constructed. Success would result in a clinical gene therapy trial. Based on the recent discovery at FCCC of a promotor which shows specificity of function in human ovarian cancer, the goal of this proposal is to construct such vectors and preclinically evaluate their efficacy and safety by accomplishing the following specific aims:
Specific Aim 1. Develop and evaluate a replication-competent adenoviral vector expressing HSVtk. This will be accomplished by developing and testing a replicating adenoviral vector containing the HSVtk suicide gene. In a first series of experiments (proof of principal), we will study a fully replicative virus containing the HSVtk gene inserted into the E3 region in ovarian tumor models. This will begin to allow us to understand the dynamics of viral replication vs delivery of GCV.
Specific Aim 2. Develop and evaluate a replication-competent adenoviral vector expressing HSVtk that will only replicate in ovarian cancer cells. This will be accomplished by developing Ad mutants that replicate selectively in ovarian tumors using the """"""""U3"""""""" promoter developed by Dr. Hamilton and his group. These vectors will be made by disrupting the normal Ad E1a promoter region and inserting the ovarian cancer-selective promoter into this region. Since replication is dependent on early production of E1 proteins, viral replication will be limited to those cells in which the tumor specific promoter is active.
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