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We are developing HSV vectors as therapeutic agents for cancer, studying HSV interactions with cancer and normal cells, with the long-term goal being the clinical application of these vectors to patients. Our research centers on oncolytic (replication-competent) HSV vectors, which target tumor cells for destruction, yet are non-pathogenic to normal tissue.
Oncolytic HSV vectors. Tumor selectivity can be achieved by mutating HSV genes that make the virus non-permissive in 'normal cells' such as those; necessary for replication in non-dividing cells, blocking innate cellular responses or apoptosis, or involved in pathogenicity. Many of these viral mutants are 'complemented' by cellular proteins with homologous activities, and agents that alter their expression, such as induction of DNA repair, can enhance oncolytic HSV activity. Characterizing virus-tumor and –host interactions, including both anti-tumor efficacy and host pathogenicity, in animal models is an important element of these studies.
Transcriptionally-targeted HSV vectors. In this strategy, viral replication and associated cytotoxicity are restricted to a specific cell type by the regulated expression of an essential immediate-early viral gene product. A recent example is a ß-catenin/Tcf regulated oncolytic HSV, which replicates in tumor cells mutated in the Wnt signaling pathway. Such vectors also provide reagents to probe the activity of oncogenic mutations in the pathway.
Immunotherapy. The host immune response plays a complex role in therapeutic efficacy, for example acute innate responses can inhibit virus spread, whereas, activation of dendritic cells and antigen cross-presentation can prime anti-tumor adaptive immune responses, areas of active investigation. We are studying the interaction of HSV with dendritic cells and exploiting this for therapy. We are also 'arming' oncolytic HSV with transgenes that can modulate/enhance the immune response to improve therapy.
Targeting tumor as an organ. In addition to bulk tumor cells, the tumor microenvironment is composed of an array of cell types including; cancer stem-like or initiating cells, endothelial cells, inflammatory cells, and fibroblasts. We are studying glioma stem-like cells, which provide more representative tumor models and are important therapeutic targets. The tumor microenvironment is critical to tumor progression and 'armed' oncolytic HSV vectors are being developed that combine direct cell killing with expression of transgenes to inhibit tumor stroma and vasculature.
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References:
Aghi, M., Rabkin, S. D., and Martuza, R. L. DNA repair enzymes induced by temozolomide vary with MGMT expression and enhance replication of specific oncolytic HSV mutants in gliomas. J Natl Cancer Inst 2006, 98: 38-50.
Kuroda, T., Martuza, R. L., Todo, T., and Rabkin, S. D. Bacterial artificial chromosome based system for rapid gereration of transcriptionally-targeted herpes simplex virus vectors using two independent site-specific recombinases. BMC Biotech 2006, 6: 40
Liu, T-C., Zhang, T., Fukuhara, H., Kuroda, T., Todo, T., Canron, X., Bikfalvi, A., Martuza, R.,* Kurtz, A., and *Rabkin, S. D. Dominant-negative FGFR expression enhances the antitumor potency of oncolytic HSV in neural tumors. Clin Cancer Res 2006, 12: 6791-6799.
Kuroda, T., Rabkin, S.D., and Martuza, R. L. Effective treatment of tumors with strong ß-catenin/T-cell factor activity by transcriptionally targeted oncolytic herpes simplex virus vector. Cancer Res 2006, 66: 10127-10135.
Liu, TC, Wakimoto, H., Martuza, RL, Rabkin, SD. Herpes simplex virus Us3(-) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-akt-targeting molecular therapeutics. Clin Cancer Res 2007 13: 5897-5902 |
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