Oncolytic HSV and Erlotinib Inhibit Tumor Growth and Angiogenesis in a Novel Malignant Peripheral Nerve Sheath Tumor Xenograft Model
| Autor: | Timothy M. Crombleholme, Shyra J. Miller, Yonatan Y. Mahller, Maria Ripberger, Nancy Ratner, Margaret H. Collins, Sachin S. Vaikunth, Timothy P. Cripe, Mark A. Currier, Ruty Mehrian-Shai, Ya-Hsuan Hsu |
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| Rok vydání: | 2007 |
| Předmět: |
Angiogenesis
Mice SCID Nerve Sheath Neoplasms Mice 0302 clinical medicine Mice Inbred NOD Chlorocebus aethiops Drug Discovery Simplexvirus Epidermal growth factor receptor Cells Cultured In Situ Hybridization Oligonucleotide Array Sequence Analysis EGFR inhibitors Oncolytic Virotherapy 0303 health sciences Neovascularization Pathologic biology Reverse Transcriptase Polymerase Chain Reaction 3. Good health ErbB Receptors 030220 oncology & carcinogenesis Molecular Medicine Rabbits Erlotinib medicine.drug Immunoblotting Malignant peripheral nerve sheath tumor Virus Cell Line Erlotinib Hydrochloride 03 medical and health sciences Cell Line Tumor Genetics medicine Animals Humans Protein Kinase Inhibitors Vero Cells Molecular Biology 030304 developmental biology Pharmacology business.industry Genetic Therapy medicine.disease Xenograft Model Antitumor Assays Oncolytic virus Viral replication Immunology Quinazolines Cancer research biology.protein business |
| Zdroj: | Molecular Therapy. 15:279-286 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/sj.mt.6300038 |
| Popis: | Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a xenograft model of human MPNST and evaluated the antitumor effects of oHSV mutants (G207 and hrR3) and the EGFR inhibitor, erlotinib. Additive cytotoxicity of these agents was found in human MPNST cell lines, suggesting that EGFR signaling is not critical for virus replication. Mice bearing human MPNST tumors treated with G207 or hrR3 by intraperitoneal or intratumoral injection showed tumor-selective virus biodistribution, virus replication, and reduced tumor burden. oHSV injection demonstrated more dramatic antitumor activity than erlotinib. Combination therapies showed a trend toward an increased antiproliferative effect. Both oHSV and erlotinib were antiangiogenic as measured by proangiogenic gene expression, effect on endothelial cells and xenograft vessel density. Overall, oHSVs showed highly potent antitumor effects against MPNST xenografts, an effect not diminished by EGFR inhibition. Our data suggest that inclusion of MPNSTs in clinical trials of oHSV is warranted. |
| Databáze: | OpenAIRE |
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