Double Selection Approach to Achieve Specific Expression of Toxin Genes for Ovarian Cancer Gene Therapy; Final rept. 1 Nov 2004-31 Oct 2007

摘要

Gene therapy is a novel treatment modality which offers great potential for the control of carcinoma of the ovary. The efficacy of such approaches, however, is currently limited due to the inability of available gene delivery vehicles (vectors) to achieve efficient and selective gene transfer to target tumor cells. Proposed herein is a strategy to modify one candidate vector, recombinant adenovirus, such that it embodies the requisite properties of efficacy and specificity. This approach is based on targeting the delivered anti-cancer gene to tumor via two complimentary approaches. This strategy is based upon restricting the expression of the anti-cancer gene exclusively to ovarian cancer tumor cells ('transcriptional targeting') plus directing the binding of the viral vector particle exclusively to tumor cells ('transductional targeting').This 'double targeting' approach is highly novel. We have advanced this double targeting approach and shown its overall utility for improving ovarian cancer gene therapy. In the first regard, we have improved the infectivity of adenovirus (Ad) for ovarian cancer targets via a knob switch method exploiting fiber knobs of canine and ovine Ad fiber knobs. In the second instance, we have defined optimized tumor selective promoters for ovarian cancer (TSPs). Finally, we have shown that the combination of these targeting strategies can improve the overall therapeutic index of ovarian cancer gene therapy in a stringent murine model of human ovarian cancer. These studies have thus provided the framework for translation of targeting approaches to the context of human clinical trials.