ENHANCEMENT OF HSV-TK GENE THERAPY IN CANCER

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DESCRIPTION: Lack of target specificity limits our ability to provide the dose-intensity required to cure disseminated cancer with conventional systemic cytotoxic agents. In theory, increased dose-intensity could be achieved by inserting a gene that would activate a non-cytotoxic precursor to a cytotoxic form. These investigators have therefore studied adenoviral transfer of the herpes simplex virus thymidine kinase gene (HSV-tk) to malignant cells growing as ascites tumors in nude mice, thus enabling these cells to metabolize the nucleoside analog ganciclovir (GCV) to a lethal product. While this treatment prolonged survival, they were not able to cure the animals. Attempts to increase the dose intensity by increasing the dose of virus actually shortened survival, due to transduction of normal organs by the adenoviral vector. In this application, the investigators propose to improve HSV-tk gene therapy by defining the role of the promoter in the therapeutic efficacy of HSV-tk gene therapy. The Specific Aims are: (1) to increase promoter strength to enhance the dose intensity and therapeutic efficacy of HSV-tk gene therapy, (2) to distinguish among several possible causes of HSV-tk/GCV treatment failure (ineffective HSV-tk transduction of tumor cells, mutation of HSV-tk gene or loss of gene expression in tumor cells, or altered host metabolism of GCV), and (3) to enhance tumor specific expression of HSV-tk, increase dose intensity, and reduce host-toxicity by creating HSV-tk expression vectors under the control of the estrogen-response element and by utilizing adenoviral constructs with HSV-tk under the control of CEA and CA-15-3 promoters. The long-term goal is to transfer gene therapy strategies from pre-clinical model systems to the treatment of patients with cancer. The studies proposed here will identify approaches for enhancing local dose-intensity of HSV-tk gene therapy, for circumventing or overcoming resistance to this therapy, and to test the ability of cancer-specific promoters to improve therapeutic outcome.