The tumor microenvironment is increasingly recognized as an important determinant not just for tumor progression but also for effective delivery of therapeutics. Vasculature is a major component of the microenvironment of solid tumors such as malignant gliomas. We have been investigating changes induced in tumor blood vessels after oncolytic viral (OV) therapy to uncover ways to enhance this revolutionary treatment modality. Our preliminary results indicate that OV treatment of experimental gliomas resulted in: (1) increased vascular permeability and along with inflammatory cell infiltrate (2) Further our results also demonstrate the increased angiogenesis of residual disease after oncolysis. We hypothesized that the increased inflammation is deleterious to OV therapy by permitting viral clearance and the changes in tumor microenvironment after OV therapy encourage regrowth of residual disease after oncolysis. We propose to construct and test a novel Oncolytic virus which expresses Vasculostatin. Vasculostatin is a naturally occurring fragment of BAI1 with potent anti-angiogenic, anti-tumorigenic and anti-permeability properties. We hypothesize that Vasculostatin expression should reduce OV induced inflammation by suppressing vascular leakage, and would also counter the OV induced changes in tumor microenvironment by leaving in the tumor after oncolysis an angiostatic ECM environment. This would fight the angiogenic nature of the residual disease, which represent an unfortunate side effect of oncolysis. This should translate into improved therapeutic efficacy for patients suffering from brain tumors. ? ? ?
