Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths in the world, accounting for over 1 million cases annually. In the United States its incidence has increased from 1.4 (1976-80) to 2.4 (1991-95) per 100,000, which may be related to an increase in chronic hepatitis C infection, with an estimated 16,600 new cases and 14,100 deaths in 2002. Median survival of untreated HCC patients is only 7.8 months, with a 3-year survival rate of 10%. The current treatment modalities for HCC are hepatic resection, intra-tumoral ablation and orthotopic liver transplantation, which are not very effective and patient's prognosis remains poor. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents. Vesicular Stomatitis Virus (VSV) is a negative-strand RNA virus with inherent specificity for replication in tumor cells due to their attenuated anti-viral responses. VSV as an oncolytic virus is particularly appealing for its exceptionally rapid replication rate of 1-2 hours in tumor cells, such that the oncolytic effects could be maximally manifested before the onset of potentially neutralizing anti-viral immune responses in the host. We have successfully rescued a recombinant VSV vector expressing the green fluorescent protein (rVSV-GFP) and demonstrated its cytopathic effects and replication in cultured Morris rat hepatoma cells and in solitary nodules of HCC established in the livers of syngeneic Buffalo rats. We propose to investigate the molecular mechanism(s) by which VSV's inherent tumor specificity is manifested in the rat hepatoma cells. In order to assess the tumoricidal potential of VSV to treat multi-focal HCC in an immune-competent host, such a model has been developed in the livers of syngeneic Buffalo rats through mesenteric vein infusion of the Morris rat hepatoma cells. Three days after hepatic artery infusion of rVSV-GFP, extensive necrosis was apparent in multiple hepatic lesions that were also positive for GFP by flouresence analyses and VSV by immuno-histochemical staining. Importantly, the surrounding normal liver tissues were negative for VSV staining and any signs of pathology. Using this immune-competent syngeneic animal model with multi-focal HCC in the liver, we propose to test the following hypotheses: 1. rVSV, delivered through hepatic artery infusion, can be an effective oncolytic agent and prolong survival of the tumor-bearing animals with minimal toxicities; 2. Its oncolytic potential can be enhanced by incorporation of the HSV-VP22/TK fusion gene into the vector with timely administration of ganciclovir; 3. Its effectiveness can be further amplified by incorporation of a heterologous viral fusogenic membrane glycoprotein gene that will induce syncytia formation with neighboring cells and 4. Repeated administration of the oncolytic virus can be effectively applied in immune-competent animals by substituting its G gene for those from VSVs of different serotypes. Successful conduct of these pre-clinical studies will provide the scientific foundation for future development of recombinant VSV as a novel therapeutic agent for multi-focal HCC in patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100830-04
Application #
7058803
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Welch, Anthony R
Project Start
2003-05-15
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$331,447
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Altomonte, J; Wu, L; Meseck, M et al. (2009) Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells. Cancer Gene Ther 16:266-78
Altomonte, Jennifer; Wu, Lan; Chen, Li et al. (2008) Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. Mol Ther 16:146-53
Wu, Lan; Huang, Tian-gui; Meseck, Marcia et al. (2008) rVSV(M Delta 51)-M3 is an effective and safe oncolytic virus for cancer therapy. Hum Gene Ther 19:635-47
Shinozaki, Katsunori; Ebert, Oliver; Suriawinata, Arief et al. (2005) Prophylactic alpha interferon treatment increases the therapeutic index of oncolytic vesicular stomatitis virus virotherapy for advanced hepatocellular carcinoma in immune-competent rats. J Virol 79:13705-13
Shinozaki, Katsunori; Ebert, Oliver; Woo, Savio L C (2005) Eradication of advanced hepatocellular carcinoma in rats via repeated hepatic arterial infusions of recombinant VSV. Hepatology 41:196-203
Ebert, Oliver; Harbaran, Sonal; Shinozaki, Katsunori et al. (2005) Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice. Cancer Gene Ther 12:350-8
Shinozaki, Katsunori; Ebert, Oliver; Kournioti, Chryssanthi et al. (2004) Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus. Mol Ther 9:368-76
Ebert, Oliver; Shinozaki, Katsunori; Kournioti, Chryssanthi et al. (2004) Syncytia induction enhances the oncolytic potential of vesicular stomatitis virus in virotherapy for cancer. Cancer Res 64:3265-70
Ebert, Oliver; Shinozaki, Katsunori; Huang, Tian-Gui et al. (2003) Oncolytic vesicular stomatitis virus for treatment of orthotopic hepatocellular carcinoma in immune-competent rats. Cancer Res 63:3605-11
Huang, Tian-Gui; Ebert, Oliver; Shinozaki, Katsunori et al. (2003) Oncolysis of hepatic metastasis of colorectal cancer by recombinant vesicular stomatitis virus in immune-competent mice. Mol Ther 8:434-40