title: Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes.
abstract: Metastatic malignant melanoma remains one of the most therapeutically challenging forms of cancer. Here we test replication-competent vesicular stomatitis viruses (VSV) on 19 primary human melanoma samples and compare these infections with those of normal human melanocyte control cells. Even at a low viral concentration, we found a strong susceptibility to viral oncolysis in over 70% of melanomas. In contrast, melanocytes displayed strong resistance to virus infection and showed complete protection by interferon. Several recombinant VSVs were compared, and all infected and killed most melanomas with differences in the time course with increasing rates of melanoma infection, as follows: VSV-CT9-M51 < VSV-M51 < VSV-G/GFP < VSV-rp30. VSV-rp30 sequencing revealed 2 nonsynonymous mutations at codon positions P126 and L223, both of which appear to be required for the enhanced phenotype. VSV-rp30 showed effective targeting and infection of multiple subcutaneous and intracranial melanoma xenografts in SCID mice after tail vein virus application. Sequence analysis of mutations in the melanomas used revealed that BRAF but not NRAS gene mutation status was predictive for enhanced susceptibility to infection. In mouse melanoma models with specific induced gene mutations including mutations of the Braf, Pten, and Cdkn2a genes, viral infection correlated with the extent of malignant transformation. Similar to human melanocytes, mouse melanocytes resisted VSV-rp30 infection. This study confirms the general susceptibility of the majority of human melanoma types for VSV-mediated oncolysis.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Wollmann
authors.forename: John N
authors.initials: JN
authors.lastname: Davis
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.forename: Anthony N
authors.initials: AN
authors.lastname: van den Pol
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008544:Melanocytes / Q000821:virology*; D008545:Melanoma / Q000628:therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000472:pathogenicity*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D014183:Transplantation, Heterologous / Q000502:physiology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000472:pathogenicity*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
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