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HSV has many attractive features as a viral vector; the genome is very large and can accommodate large inserts, it efficiently infects most cell types both dividing and non-dividing from a broad range of species, it naturally undergoes a latent infection in neurons that causes no detectable damage to the infected cell or can undergo a lytic infection that is cytotoxic, and antiviral drugs are available to treat adverse events. Our major focus is the application of oncolytic (replication-competent) HSV for the treatment of cancer. Tumor selectivity is achieved by mutating the virus so that it is permissive in cancer cells, but not "normal" cells, thereby targeting tumors for destruction while being non-pathogenic. These viral genes typically facilitate replication in non-dividing cells, overcome innate host antiviral responses, and/or are involved in pathogenicity. Our general approach is to identify and mutate suitable viral genes, characterize the oncolytic HSV vectors in vitro, test their efficacy and mechanism of action in tumor models in vivo, confirm their safety, and finally translate to the clinic. We utilize a variety of animal tumor models; human xenografts in immune-deficient mice, syngeneic mouse tumor implants, or spontaneously arising tumors in transgenic mice.
Areas of research focus:
Development of New Oncolytic HSV Vectors
We are continuing to construct new oncolytic HSV vectors and explore the consequences of different mutations on HSV biology in cancer cells. Because of the interaction of some HSV genes with cellular survival pathways, mutations in these genes can sensitize infected cells to drugs targeting these pathways (related research article). A technical advance has been the generation of HSV-BAC (bacterial artificial chromosome) plasmids that can be manipulated in bacteria and biochemically (related research article). These constructs are useful for rapidly inserting a variety of therapeutic transgenes into defined sites in the HSV genome and to generate transcriptionally-targeted vectors.
Transcriptionally-Targeted Oncolytic HSV
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 (ICP4). An example of such a construct is a β-catenin/Tcf regulated oncolytic HSV that replicates in cancer cells mutated in the Wnt signaling pathway, such as colorectal cancer (related research article).
As many cancer patients are already receiving a variety of anticancer drugs, we have been examining the interactions between oncolytic HSV vectors and these drugs and novel small-molecule inhibitors. The combination often achieves more efficient cell killing than either agent alone, often through synergistic interactions, and we are exploring the mechanisms underlying these HSV/drug interactions (related research article). This has revealed a number of different mechanisms that depend upon the mutations present in the oncolytic HSV and the drug effects, such as; increased virus replication due to upregulation of cellular proteins complementing virus mutations with dilazep and temozolomide (related research article #1 and #2), inhibition of cyclin D1 with HDAC inhibitors (related research article), and increased apoptosis with PI3K/Akt inhibitors (related research article #1 and #2).
"Armed" Vectors Targeting the Tumor Microenvironment
In addition to cancer cells, the tumor microenvironment is composed of an array of cell types including: endothelial cells of the neovasculature, inflammatory cells and fibroblasts in the stroma. 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 (related research article).
Oncolytic HSV 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, with oncolytic HSV acting as an "in situ vaccine." We are studying the interaction of HSV with dendritic cells and exploiting this for therapy (related research article). We are also "arming" oncolytic HSV with transgenes that can modulate/enhance the immune response to improve therapy, such as expressing immune-modulatory genes (i.e., cytokines) and xenogeneic tumor antigens (related research article).
Glioblastoma Stem Cells
Cancer stem or tumor-initiating cells have recently been described for a number of solid tumors, including glioblastoma. We have been isolating and characterizing glioblastoma stem cells (GSCs) from patient tumor specimens (related research article). GSCs are very efficient at forming tumors in the brain in immune-deficient mice and their xenografts histologically recapitulate the features present in the corresponding patient tumor. Thus they provide an excellent model for the development of novel therapeutics and oncolytic HSV against glioblastoma.
Virotherapy for Prostate Cancer
We have had a long-standing interest in the use of oncolytic HSV to treat prostate cancer, and have used a wide variety of tumors models, including: transgenic mice (related research article), lung metastases (related research article), and primary organotypic cultures (related research article). Oncolytic HSV expressing IL12 is particularly effective for prostate cancer, enhancing anti-tumor immune responses and anti-angiogenesis.
Virotherapy for Tumors Arising in Neurofibromatosis
Neurofibromatosis (Nf) types 1 and 2 are inherited cancer syndromes causing tumors of the peripheral nervous system. They are relatively benign tumors except for malignant peripheral nerve sheath tumors (MPNST), which arise in a small proportion of NF1 patients and are usually lethal. We have isolated cancer stem-like cells from MPNST (read related article).
Molecular Neurosurgery Lab
Richard B. Simches Research Center
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