title: Enhancement of the proapoptotic properties of newcastle disease virus promotes tumor remission in syngeneic murine cancer models.
abstract: Newcastle disease virus (NDV) is considered a promising agent for cancer therapy due to its oncolytic properties. These include preferential replication in transformed cells, induction of innate and adaptive immune responses within tumors, and cytopathic effects in infected tumor cells due to the activation of apoptosis. To enhance the latter and thus possibly enhance the overall oncolytic activity of NDV, we generated a recombinant NDV encoding the human TNF receptor Fas (rNDV-B1/Fas). rNDV-B1/Fas replicates to similar titers as its wild-type (rNDV-B1) counterpart; however, overexpression of Fas in infected cells leads to higher levels of cytotoxicity correlated with faster and increased apoptosis responses, in which both the intrinsic and extrinsic pathways are activated earlier. Furthermore, in vivo studies in syngeneic murine melanoma models show an enhancement of the oncolytic properties of rNDV-B1/Fas, with major improvements in survival and tumor remission. Altogether, our data suggest that upregulation of the proapoptotic function of NDV is a viable approach to enhance its antitumor properties and adds to the currently known, rationally based strategies to design optimized therapeutic viral vectors for the treatment of cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Salamanca, Salamanca, Spain. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sara
authors.initials: S
authors.lastname: Cuadrado-Castano
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Juan
authors.initials: J
authors.lastname: Ayllon
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Mena
authors.initials: M
authors.lastname: Mansour
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Janis
authors.initials: J
authors.lastname: de la Iglesia-Vicente
authors.affiliation: Department of Oncological Sciences, Immunology Institute and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jordan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Shashank
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Adolfo.Garcia-Sastre@mssm.edu.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Salamanca, Salamanca, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Villar
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D041681:NIH 3T3 Cells; D009522:Newcastle disease virus / Q000235:genetics / Q000502:physiology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D014709:Vero Cells; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor