Primary brain tumors (mainly malignant gliomas, medulloblastomas and ependymornas) have become the main cause of death from cancer in children and young adults. Hypoxia is a physiological difference between normal and tumor tissue. We propose to exploit this difference to construct a novel type of cancer therapy adenovirus. We will conditionally regulate the replication ability of an adenovirus by placing the adenoviral EIA gene under the control of an exogenous hypoxia-regulated promoter (HYPR-Ad). Since adenoviruses have a cytolytic cycle, the selective replication of adenoviruses within hypoxic tumor cells will lead to oncolysis. Moreover, we will augment the antitumor capability of this oncolytic: virus by having it function as a therapeutic gene delivery vehicle. We will introduce into the HYPR viral vector an expression cassette for the angiogenesis inhibitor thrombospondin-1 (HYPRA-Ad). The production of this inhibitor by infected hypoxic cells will generate a field effect that should counteract the action of the angiogenic stimulators released by these cells in response to hypoxia. In addition, it should reduce the expansion of noninfected and normoxic tumor cells since they will not be able to recruit new vascular supply. These recombinant adenoviruses will be studied for their ability to infect, replicate, and induce cytolysis of cells derived from pediatric glioma, medulloblastoma and ependymoma under normoxic and hypoxic conditions in vitro. Subsequently, the therapeutic efficacy of these viruses against xenografts of these pediatric brain tumors will be examined, in both subcutaneous and intracerebral models in immunocompromised (nulnu) mice. The tumor therapy approach presented in this proposal is novel in that these viruses can provide direct oncolytic therapy as well as deliver adjuvant gene therapy. Although these viruses have broad applicability to treat ALL cancer types which develop hypoxia, regardless of their tissue of origin and genetic composition, funding of this application will enable us to specifically develop this strategy to treat/cure pediatric brain tumors. The translation of these preclinical studies have the potential to directly benefit human health by improving the survival of children and adults with cancer.
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