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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS041403-03
Application #
6629354
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Finkelstein, Robert
Project Start
2001-05-03
Project End
2004-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$190,000
Indirect Cost
Name
Emory University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Post, Dawn E; Sandberg, Eric M; Kyle, Michele M et al. (2007) Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4. Cancer Res 67:6872-81
Post, Dawn E; Shim, Hyunsuk; Toussaint-Smith, Esra et al. (2005) Cancer scene investigation: how a cold virus became a tumor killer. Future Oncol 1:247-58
Kaur, Balveen; Brat, Daniel J; Devi, Narra S et al. (2005) Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24:3632-42
Post, Dawn E; Fulci, Giulia; Chiocca, E Antonio et al. (2004) Replicative oncolytic herpes simplex viruses in combination cancer therapies. Curr Gene Ther 4:41-51
Kaur, Balveen; Tan, Chalet; Brat, Daniel J et al. (2004) Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 70:229-43
Brat, Daniel J; Castellano-Sanchez, Amilcar A; Hunter, Stephen B et al. (2004) Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 64:920-7
Brat, Daniel J; Van Meir, Erwin G (2004) Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84:397-405
Chu, Roland L; Post, Dawn E; Khuri, Fadlo R et al. (2004) Use of replicating oncolytic adenoviruses in combination therapy for cancer. Clin Cancer Res 10:5299-312
Van Meir, Erwin G; Bellail, Anita; Phuphanich, Surasak (2004) Emerging molecular therapies for brain tumors. Semin Oncol 31:38-46
Yang, L; Cao, Z; Li, F et al. (2004) Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Ther 11:1215-23

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