Recent data from our laboratory has shown that vesicular stomatitis virus, VSV, a relatively non-pathogenic, negative-stranded RNA virus, can selectively induce the cytolysis of malignant cells, but not normal cells, through the induction of apoptotic cell death. VSV appears able to selectively replicate in transformed cells since these hosts exhibit the hallmarks of a flawed interferon (IFN) system, which is essential for preventing VSV replication. The simple genetic constitution of VSV, lack of any known transforming properties, extensive immunobiology data and the ability to genetically manipulate the organism affords an ideal opportunity to further enhance the oncolytic potential of this innocuous virus. Thus, aside from preferentially targeting malignant cells and possessing direct antitumor activity, VSV recombinants could be generated that could increase a tumors susceptibility to chemotherapeutic agents and/or the host immune response. Collectively, our data demonstrates that VSV could provide a promising and exciting approach to cancer therapy.
Aim I is to confirm possible defects in the interferon and other pathway(s) such as the regulation of translation in malignant cells, which may be mechanistically responsible for allowing VSV to exert its oncolytic activity.
Aim II will further evaluate the efficacy and safety, in tumor therapy, of recombinant VSVs that express genes that may facilitate greater oncolytic ability, such as the IFN-beta gene. Our novel data should provide information on the ability of rVSVs to function as a safe therapy for the potential treatment of Cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095924-04
Application #
7090814
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Hecht, Toby T
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$296,249
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Konno, Hiroyasu; Chinn, Ivan K; Hong, Diana et al. (2018) Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING. Cell Rep 23:1112-1123
Ahn, Jeonghyun; Xia, Tianli; Rabasa Capote, Ailem et al. (2018) Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells. Cancer Cell 33:862-873.e5
Heiber, Joshua F; Barber, Glen N (2011) Vesicular stomatitis virus expressing tumor suppressor p53 is a highly attenuated, potent oncolytic agent. J Virol 85:10440-50
Heiber, Joshua F; Xu, Xiang-Xi; Barber, Glen N (2011) Potential of vesicular stomatitis virus as an oncolytic therapy for recurrent and drug-resistant ovarian cancer. Chin J Cancer 30:805-14
Elsby, Rachel; Heiber, Joshua F; Reid, Peter et al. (2011) The alpha subunit of eukaryotic initiation factor 2B (eIF2B) is required for eIF2-mediated translational suppression of vesicular stomatitis virus. J Virol 85:9716-25
Capo-chichi, Callinice D; Yeasky, Toni M; Heiber, Joshua F et al. (2010) Explicit targeting of transformed cells by VSV in ovarian epithelial tumor-bearing Wv mouse models. Gynecol Oncol 116:269-75
Andrews, Nicolas P; Pack, Christopher D; Vezys, Vaiva et al. (2007) Early virus-associated bystander events affect the fitness of the CD8 T cell response to persistent virus infection. J Immunol 178:7267-75
Greidinger, Eric L; Zang, YunJuan; Jaimes, Kimberly et al. (2006) A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 54:661-9