): Pulmonary and bone metastases occur in a wide variety of urologic cancers and account for a majority of morbidity and mortality experienced by these patients. The goals of this proposal are focused on improving adenoviral cancer gene therapy by increasing the delivery of a therapeutic gene to multiple tumor sites in patients with metastatic disease and second to restrict the therapeutic gene transcription and subsequent protein expression to the targeted tumor cells. These goals will accomplished by 1) concentrating the viral delivery to tumor sites with locoregional delivery, 2) allowing for tumor-restricted therapeutic toxic gene expression with tumor-specific promoters, and 3) modifying the adenoviral fiber protein tropism toward tumor cells using bi-specific antibodies in experimental models of human renal cell carcinoma pulmonary metastases and in human prostate cancer osseous metastases. The success of this proposal will lead to the rapid translation of these concepts and methodologies for the development of rational clinical protocols for the treatment of urologic cancer metastases and potentially cancer metastases of other cancers.
In Specific Aim 1, we will test the hypothesis that locoregional delivery can concentrate the virus, increase viral exposure and subsequent reporter gene expression to the targeted sites and that tumor-specific promoters can r e s trict the gene transcription and protein expression of reporters specifically to targeted tumor cells residing at metastatic sites. Both hypotheses will be tested in animal models mimicking human renal cell carcinoma pulmonary metastases and human prostate cancer osseous metastases.
Specific Aim 2 will further address the hypotheses of Aim 1 by comparing therapeutic efficacy and potential toxicity of locoregional delivery of therapeutic toxic genes using either tissue-specific or universal promoters.
Specific Aim 3 will test the hypothesis that the adenoviral tropism can be modified preferentially towards tumor cells by coating the adenovirus with conjugated anti-viral and anti-tumor monoclonal antibodies. Overall, the objective of this proposal is to apply and sharpen the knowledge gained by the applicant during his residency and fellowship training to develop novel and relevant therapeutic approaches for the eradication of metastatic deposits of both renal and prostate cancer.
