Oncolytic viral therapy is a promising biological treatment that relies on attenuated viruses with cancer cell specific replication and lysis with minimal replication or lysis in non neoplastic tissue. While this novel biological therapy is currently being evaluated for safety and efficacy in clinical trials, its impact on the microenvironment and the microenvironments response to OV therapy has tremendous implications on viral propagation and efficacy. The ultimate goal of this proposal is to evaluate the role of microvesicle-derived viral transcripts in oncolytic virotherapy of experimental glioma. In our pilot data, we have discovered that OV-infected glioma cells release microvesicles that appear to be preferentially enriched with viral transcripts, responsible for initiating the transcriptional cascade that turns on the infecting HSV genome. This is a novel finding whose relevance derives form additional published data indicating a role for microvesicles derived from virally infected cells priming neighboring cells for a productive infection by progeny virions. In this proposal, we will thus focus on evaluating whether microvesicle-derived viral and key cellular transcripts prime the microenvironment of the infected glioma to allow for more efficient replication and distribution of the OV and therapeutic transgenes carried by the OV. If shown to be valid, this hypothesis would thus suggest avenues to improve the efficacy of virotherapy. In addition we will evaluate whether RNA/proteins in microvesicles released by virally infected tumors can serve as markers of therapeutic response in vivo using a GBM mouse model. We will be actively interacting with Projects 2 and 3 for their expertise and help in measuring RNAs and proteins, respectively, in microvesicles, and with Core C which will be providing the GBM mouse models. We will also provide serum derived microvesicles harvested in our studies to projects 2, and 3. Biostatistical and neuropathological oversight will be provided by Core A.
The overall goal of this proposal is to understand the significance and content of secreted microvesicles after OV treatment. The results from this project will elucidate the feasibility of using microvesicle content as biomarkers to predict OV efficacy in patients.
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