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Targeting Retrovirus Replication for Gene Therapy of Breast Cancer
Recently there has been a resurgence of interest in the use of replication-competent viruses that take advantage of impaired host defenses in tumor cells to achieve oncolysis. Most previous strategies for gene therapy of solid tumors such as breast cancer have involved the use of replication-defective viral vectors, but significant problems were encountered due to lack of adequate transduction levels and limited diffusion within the tumor. Gene transfer using replicating viruses is more efficient, as each successfully transduced tumor cell itself becomes a virus-producing cell, initiating further infection events. However, lack of viral persistence, leading to only transient suppression of tumor growth, is now recognized as one of the major obstacles to success of cancer virotherapy. To address this issue, we have devised a novel replication-competent retrovirus (RCR) vector which, due to its characteristic ability to achieve stable genomic integration only in actively dividing host cells, is capable of highly efficient, selective, and persistent gene delivery throughout entire solid tumors in vivo, resulting in significant inhibition of tumor growth and long-term survival.
Until now, the use of such RCR vectors has rarely been contemplated for gene therapy due to the risks associated with uncontrolled virus spread. Targeting RCR specifically and exclusively to tumor cells would limit and control the replicative process while minimizing any risk to normal cells, and would represent a significant improvement in vector design. We have previously demonstrated that prostate-specific regulatory elements engineered into the RCR promoter region can direct highly specific replication and transgene expression only in prostate cancer cells.
In this proposal, we propose to use the same principle to construct and test RCR vectors targeted to human breast cancer cells, using mammary- or mammary carcinoma-specific promoters. Whether such targeting of RCR vectors expressing suicide genes or immunostimulatory cytokine genes will prevent extratumoral spread and enhance safety will first be assessed after intratumoral injection in a model for non-invasive mass reduction of locally advanced disease, and subsequently, we will test whether systemic administration of targeted RCR vectors has the potential to achieve therapeutic efficacy in models of distant site metastasis.
Gene therapy is a promising new approach in which genes delivered directly to cancer cells serve as the blueprint for therapeutic proteins that will kill the cells from within, or will provoke an immune response so that the body rejects the cancer cells. However, while this approach promises to be more effective with fewer side effects than current chemotherapy, the efficiency of delivering genes has proven to be a major obstacle to the success of gene therapy. This project aims to improve the efficiency of gene delivery to breast cancer cells and overcome this obstacle.
Many strategies for gene therapy have involved the use of certain viruses as vehicles ("vectors") for gene delivery, because viruses have evolved efficient ways to insert their genes into human cells. However, by removing the viral genes that naturally allowed the virus to spread from cell to cell, these vectors were made safer but it was found that the efficiency of these disabled viruses in infecting tumors and delivering genes are too low to be therapeutically useful.
Here we propose to use modified virus vectors that are less disabled, and retain the ability to spread from cell to cell. We have already shown that such vectors can indeed achieve highly efficient delivery of therapeutic genes to breast cancer cells, but also raise safety concerns related to the consequences of uncontrolled spread of the virus vectors to normal cells. In order to prevent uncontrolled spread, we propose to target these virus vectors specifically to breast cancer cells by introducing mammary cell-specific gene regulation sequences into them. This targeting strategy will now make it possible to limit the spread of the virus vectors exclusively to breast cancer cells, while minimizing any risk to normal cells.
This "virus vs. cancer" strategy thus takes advantage of the amplification process inherent in the spread of virus from cell to cell, and by targeting the virus infection selectively to breast cancer cells, represents an approach that will be useful both as a non-invasive method for local mass reduction and will have the potential to effectively treat widespread metastatic disease.