Glioblastoma are aggressive and invasive brain tumors that generally lead to death within a year of diagnosis. No cure is available, and current treatments prolong life by only a few months. In the current application, we propose to study the potential use of vesicular stomatitis virus (VSV) to selectively infect and kill these brain tumors. We have developed recombinant VSVs that selectively infect human glioblastoma and not control cells in vitro, and target glioblastoma cells transplanted into the mouse brain. As these viruses are replication-competent, after killing the first round of glioblastoma, progeny viruses are released which cytolytically infect more glioblastoma cells. Experiments are based on in vitro use of human and mouse glioblastoma and control cells, and on human or mouse tumor cells transplanted into the mouse brain. Four sets of experiments are planned. In the first set of experiments, recombinant VSVs will be used to test the hypothesis that enhancing the cellular interferon response or slowing replication will selectively protect normal, but not brain tumor, cells. VSVs that selectively infect glioblastoma will then be used with in vivo experiments in which human glioblastoma cells that express a red reporter gene are transplanted into the brains of SCID mice, or red mouse glioblastoma is transplanted into the normal immunocompetent mouse brain. VSV will be administered either directly into the brain tumor, or by systemic injection into the tail vein to test the hypothesis that the virus will selectively infect and kill the glioblastoma cells within the brain with little spread to the normal brain tissue. To increase the safety profile related to oncolytic viruses in the brain, a third set of in vitro and in vivo experiments will test several antiviral drugs (interferons, ribavirin, aspirin, polylC, IL-12) that have been reported to be effective in controlling viral infections to determine which is the most efficacious in blocking possible VSV infections of normal brain. The hypothesis that peripheral VSV immunization will attenuate a later cerebral infection by recombinant VSV will be tested. A final set of experiments will test the hypothesis that recombinant VSV will show no, or relatively little infection and replication in non-tumor slices of the human brain in vitro. The primary goal of these studies is to test the efficacy and safety of variant oncolytic VSVs as the first step as a potential treatment for currently incurable human brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124737-05
Application #
8055531
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Welch, Anthony R
Project Start
2007-08-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$305,017
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wollmann, Guido; Paglino, Justin C; Maloney, Patrick R et al. (2015) Attenuation of vesicular stomatitis virus infection of brain using antiviral drugs and an adeno-associated virus-interferon vector. Virology 475:1-14
van den Pol, Anthony N; Ding, Siyuan; Robek, Michael D (2014) Long-distance interferon signaling within the brain blocks virus spread. J Virol 88:3695-704
Paglino, Justin C; Andres, Wells; van den Pol, Anthony N (2014) Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells. J Virol 88:4932-42
van den Pol, Anthony N (2013) Polio, still lurking in the shadows. J Neurosci 33:855-62
Wollmann, Guido; Davis, John N; Bosenberg, Marcus W et al. (2013) Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes. J Virol 87:6644-59
van den Pol, Anthony N; Davis, John N (2013) Highly attenuated recombinant vesicular stomatitis virus VSV-12'GFP displays immunogenic and oncolytic activity. J Virol 87:1019-34
Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N (2012) LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells. J Virol 86:7280-91
Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N (2012) Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates. Cancer J 18:69-81
Paglino, Justin C; van den Pol, Anthony N (2011) Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways. J Virol 85:9346-58
Wollmann, Guido; Rogulin, Vitaliy; Simon, Ian et al. (2010) Some attenuated variants of vesicular stomatitis virus show enhanced oncolytic activity against human glioblastoma cells relative to normal brain cells. J Virol 84:1563-73

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