THER-07. INHIBITION OF THE RAS SIGNALING ENHANCES VIRAL ONCOLYSIS IN MALIGNANT GLIOMAS

Pediatric malignant glioma indicates rapid proliferation, widely infiltrative properties and resistance to various therapies, and carries a very poor prognosis. There are methods of using virus within novel therapies under development against malignant neoplasms, which have been studied for many years already. We examined the treatment with sunitinib or GW5074 to our experimental model of vaccinia virus therapy for malignant glioma, and then evaluated changes in the tumoricidal activity, the viral infectivity, and the impact on the Ras signaling pathway. Glioma cells (U251MG, LN229, LN18, rat C6) infected with vaccinia virus was fatal, in its course of death, apoptosis and autophagy were induced. The activity of Ras signaling in vaccinia-infected cells heightened in the early stage and declined in the late stage Inhibition of the Ras signaling pathway at the early stage of viral infection prevented vaccinia virus replication, while viral oncolysis was not inhibited when the pathway was blocked after sufficient viral spread. Glioma cells infected with vaccinia virus are led to cell death. Vaccinia virus regulates Ras or other survival signaling pathways in the infected cells. It enhances the signaling in the early stage (viral replicative period), however suppresses in the later stage (virus-releasing stage). Inhibition of the Ras signaling pathway at the early stage of viral infection prevents vaccinia virus from replicating, while viral oncolysis appears to be accelerated when the pathway was blocked after sufficient viral reproduction.