title: Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model.
abstract: Rhabdomyosarcoma (RMS), a neoplasm characterized by undifferentiated myoblasts, is the most common soft tissue tumour in children. Therapeutic resistance is common in RMS and is often caused by acquired defects in the cellular apoptotic program. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 is overexpressed in human primary RMS tumours and in patient-derived RMS cell lines where it drives resistance to apoptosis. In this study, we investigated whether inflammatory cytokine production triggered by activators of innate immunity synergizes with LCL161 to induce bystander killing of RMS cells in vitro and in vivo. Indeed, we show that innate immune stimuli (oncolytic virus (VSVΔ51-GFP), interferon γ (IFNγ), and tumour necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs in vitro to reduce cell viability in the Kym-1 RMS cancer cell line. Other human RMS cell lines (RH36, RH41, RD, RH18, RH28, and RH30) and the murine RMS cell line 76-9 are resistant to treatment with LCL161 alone or in combination with immune stimulants in in vitro cell viability assays. In contrast, we report that the combination of LCL161 and VSVΔ51-GFP reduces tumour volume and prolongs survival in a 76-9 syngeneic murine model. Our results support further exploration of the combined use of IAP antagonists and innate immune stimuli as a therapeutic approach for RMS cancers.
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Dobson
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Thet
authors.initials: T
authors.lastname: Naing
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Beug
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Mame D
authors.initials: MD
authors.lastname: Faye
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Janelle
authors.initials: J
authors.lastname: Chabot
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: St-Jean
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Walker
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Eric C
authors.initials: EC
authors.lastname: LaCasse
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Korneluk
authors.affiliation: Molecular Biomedicine Program, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.|Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D013844:Thiazoles / Q000494:pharmacology*; D047368:Tumor Burden; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D050856:Interferon Regulatory Factor-1; C574246:LCL161; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha
keywords: Smac mimetic; immunotherapy; oncolytic virus; rhabdomyosarcoma