title: Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors.
abstract: Only a subset of cancer patients inoculated with oncolytic herpes simplex virus (oHSV) type-1 has shown objective response in phase 1 and 2 clinical trials. This has raised speculations whether resistance of tumor cells to oHSV therapy may be a limiting factor. In this study, we have identified established and patient derived primary glioblastoma multiforme (GBM) stem cell lines (GSC) resistant to oHSV and also to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that has recently shown promise in preclinical and initial clinical studies. We created a recombinant oHSV bearing a secretable TRAIL (oHSV-TRAIL) and hypothesized that oHSV-TRAIL could be used as a cancer therapeutic to target a broad spectrum of resistant tumors in a mechanism-based manner. Using the identified resistant GBM lines, we show that oHSV-TRAIL downregulates extracellular signal-regulated protein kinase (ERK)-mitogen-activated protein kinase (MAPK) and upregulates c-Jun N-terminal kinase (JNK) and p38-MAPK signaling, which primes resistant GBM cells to apoptosis via activation of caspase-8, -9, and -3. We further show that oHSV-TRAIL inhibits tumor growth and invasiveness and increases survival of mice bearing resistant intracerebral tumors without affecting the normal tissues. This study sheds new light on the mechanism by which oHSV and TRAIL function in concert to overcome therapeutic-resistance, and provides an oncolytic virus based platform to target a broad spectrum of different cancer types.
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Aayush S
authors.initials: AS
authors.lastname: Agarwal
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhere
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kuroda
authors.forename: Randa
authors.initials: R
authors.lastname: Kasmieh
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D050130:Oncolytic Virotherapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human