Ovarian carcinoma is the fourth leading cause of cancer death in the female population and the most fatal gynecologic malignancy. Due primarily to the lack of effective screening strategies and the deficiency of signs and symptoms in patients with early-stage disease, a high fatality rate persists. Despite advances in surgical technique and modern chemotherapy, long-term survival for most patients with advanced ovarian carcinoma has remained at approximately 15% to 30% over the past 20 years. Clearly, more effective treatment strategies are needed for this disease.
Gene therapy represents a novel investigational therapeutic approach for the treatment of ovarian cancer. Drs. Coukos and Rubin have written a comprehensive review of the current vectors available in the treatment of ovarian cancer and the gene therapy strategies in which these vectors are employed. It is clear that the major obstacles to successful gene therapy are the low efficacy and specificity of gene delivery and the potential toxicity. The authors address these obstacles, in one fashion or another, with each of the approaches they describe. We would like to discuss our approach to these issues by way of example, focusing on adenovirus as the vector of choice.
Enhancing Infectivity of the Virus
Results from preliminary human clinical gene therapy trials for ovarian cancer have uniformly demonstrated the extremely limited efficacy of current-generation vector systems in accomplishing tumor cell modification or death, as summarized in the article by Drs. Coukos and Rubin. With respect to adenovirus, this limitation is primarily due to the fact that ovarian cancer primary tumor cells are relatively resistant to infection. This resistance occurs mostly as a result of low levels of the coxsackie/adenovirus receptor on the surface of ovarian cancer cells. Therefore, enhancing infectivity of the virus is of utmost importance.
As the authors mention, modifying the viral tropism by incorporating the Arg-Gly-Asp (RGD) peptide into the HI loop of the knob has consistently demonstrated coxsackie/adenovirus receptor-independent gene transfer to primary ovarian cancer cells that is two to three orders of magnitude higher than that observed with an unmodified adenovirus vector. This modification allows the adenovirus to use cell surface integrin receptors, in addition to the common adenovirus entry pathway via coxsackie/adenovirus receptors. Although the RGD-modified adenovirus vector exhibits preferential gene transfer to primary ovarian cancer cells as opposed to human mesothelial tissue, integrins are ubiquitously expressed (albeit to differing degrees, depending on the cell type). Therefore, while this RGD motif efficiently enhances infectivity in ovarian cancer cells, it may not allow for the most stringent control of specificity.
As discussed in the article, various vector strategies that exploit different aspects of tumor biology are being used in tumor-specific gene therapy. These approaches to achieving tumor-specific gene expression have met with varying degrees of success. Our group has been working on developing vectors that use tumor-specific promoter elements to restrict gene expression or adenovirus replication. In the latter instance, conditionally replicative adenovirus agents have been created by placing an essential adenovirus replication gene under the control of a tumor-specific promoter.