This proposal is designed to transition the primary investigator, Dawn Post, to an independent research scientist by developing a separate line of research related to her current project under the guidance of a mentor. Her research interests are to design and evaluate the therapeutic efficacy of novel replication competent oncolytic viruses for tumor therapy using preclinical cancer models with the goal of translating these findings to the clinical setting. In this study, we propose to generate novel Adenovirus (Ad) and Herpes-Simplex-Virus-1 (HSV) vectors whose cytolytic replication cycle is restricted to hypoxic tumor cells and that deliver the anti-tumorigenic interleukin-4 (IL-4) and thrombospondin 1 (TSP-1) genes. The therapeutic potential of these viruses for brain tumor treatment will then be examined using experimental glioma models. Hypoxia, a reduction in the partial pressure of oxygen is a hallmark of most solid tumors. We will exploit this difference between normal and tumor tissue to achieve tumor-specific targeting of viral replication and therapeutic gene expression using hypoxia/HIF-responsive promoters that we previously designed. We have already used one of these promoters to control the initiation of Ad replication thereby creating a hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad#1). IL-4 is a cytokine that induces a host immune response against the tumor and suppresses tumor angiogenesis. TSP-1 is an anti angiogenic protein that induces endothelial cell apoptosis and inhibits endothelial cell proliferation, migration, and formation into functional vessels. A trimodal gene therapy virus strategy consisting of viral mediated lysis of hypoxic cells, immunogene, and anti-angiogenic therapies has not been designed or tested to date and has great potential for eradicating tumors such as gliomas that have widespread areas of hypoxia and immunosuppressive and angiogenic activity. The hypothesis is that conditional replication of these viruses will lead to death of hypoxic tumor cells via the viral lytic cycle while expression of IL-4 and TSP-1 should further inhibit tumor growth by targeting normoxic tumor cells, the tumor microvasculature, and non-infected hypoxic tumor cells. These viruses can be used as a therapy for a broad range of tumors types that develop hypoxia or active HIF. The translation of these preclinical studies has the potential to directly benefit human health by improving the survival of cancer patients. ? ?
