The ultimate goal of this proposal is to understand extracellular barriers to efficient spread of oncolytic viruses and to develop a novel oncolytic virus to enhance therapy of brain tumors. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from the 5 clinical trials in patients with malignant glioma have shown the relative safety of this novel treatment modality. However evidence for significant efficacy remains to be established. Inefficient viral dispersal through the tumor interstitium can lead to poor viral spread hence not permitting efficient tumor cell infection and oncolysis. Efforts to increase viral spread within the tumor should lead to improved efficacy. We believe that glioma extracellular matrix (ECM) poses a significant barrier for efficient viral spread through the tumor, and hence limits its efficacy. In our preliminary experiments we have tested the effect of an ECM modulating enzyme on OV dispersal in glioma. The use of proteases to enhance viral spread has been tested and has shown efficacy in subcutaneous tumor models. However since the expression of proteases in the brain can result in toxicity related to hemorrhaging, they have not been tested for efficacy in intracranial gliomas. More recently co-administration of hyaluronidase with adenovirus has shown increased viral spread and therapeutic efficacy against subcutaneous tumors in mice. However the expression of hyaluronidase elicits astrocytic reactivity which limits its usage for inti'acranial gliomas. Here we propose to create a novel OV that can selectively infect and destroy glioma celjs and also expresses a previously untested glioma ECM modulating enzyme to enhance viral spread. Previous studies have shown that even repeated injections of this purified enzyme within the rat brain resulted in no toxicity.. We believe this study is highly significant as the use of such an ECM modulating enzyme to enhance OV spread and efficacy has not been previously tested.
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