title: Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yonatan Y
authors.initials: YY
authors.lastname: Mahller
authors.forename: Sachin S
authors.initials: SS
authors.lastname: Vaikunth
authors.forename: Mark A
authors.initials: MA
authors.lastname: Currier
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Miller
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ripberger
authors.forename: Ya-Hsuan
authors.initials: YH
authors.lastname: Hsu
authors.forename: Ruty
authors.initials: R
authors.lastname: Mehrian-Shai
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D050130:Oncolytic Virotherapy / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics* / Q000378:metabolism; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors