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Gene Therapy for Ovarian Cancer

Gene Therapy for Ovarian Cancer

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.

Tumor-Specific Promoters

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.

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