Onkolytic Herpes Virus in hypoxic tumor tissue

Hypothesis: Viral oncolytic therapy is under intense investigation as a novel anticancer strategy. Oncolytic herpes viruses can replicate within the hypoxic environment of tumors and produce killing of cancers resistant to conventional therapy. Furthermore, viruses can be engineered to have replication-enhancing or cytotoxic proteins triggered by selective devascularization of tumors to more selectively kill tumors while sparing normal tissues. Specific Aims 1. Determine if oncolytic viruses can replicate in the hypoxic environment and determine the cellular determinants of viral replication in the hypoxic environment. Justification: Most solid tumors outgrow their nutrient blood supply. Viable tumors in these hypoxic regions have been shown to be resistant to standard chemotherapy. Oncolytic viral therapy seeks to kill cancer by exploiting the normal viral life cycle. In this regard, genetically engineered herpes viruses (HSV) are promising agents, capable of producing highly selective killing of cancers of many types. The studies in this aim seek to determine if oncolytic HSV may infect, replicate within, and lyse tumors cell under conditions of hypoxia. 2. Determine if amplicon-mediated, selective replacement of viral genes under control of hypoxia inducible regulatory elements may enhance viral replication in conditions of hypoxia. Justification: It has been previously shown that replication incompetent herpes amplicon vectors can be used to efficiently infect and introduce genes of interest into tumor cells already infected with oncolytic herpes viruses. In this specific aim, we seek to determine if amplicon vectors carrying UL39 or 134.5 under control of hypoxia inducible factor-1 (HIF) regulatory elements will enhance oncolytic viral replication under conditions of hypoxia. 3. Determine if novel mutant oncolytic viruses constructed with UL39 or 134.5 controlled by HIF regulatory elements will more vigorously replicate within and lyse tumor cells in the hypoxic environment. Determine if therapeutically inducible hypoxia of liver tumors can be exploited to further enhance virally mediated anti-tumor actions and to more specifically target tumors. Justification: One treatment for hepatic tumors is to embolize the hepatic artery to selectively devascularize tumors, which exaggerates tumor hypoxia, and increases tumor death. In this aim, we seek to determine if such selective dearterialization and the resultant enhancement of tumor hypoxia will further enhance anti-tumor actions of novel oncolytic viruses whose replication may be conditional on hypoxia. In this way we seek to determine if the combined use of dearterialization and hypoxia-responsive oncolytic viruses will more specifically target liver tumors, improving efficacy while enhancing safety.