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Oncolytic virus synergizes with Smac mimetic compounds to induce rhabdomyosarcoma cell death in a syngeneic murine model

Christine C. Dobson, Thet Naing, Shawn T. Beug, Mame D. Faye, Janelle Chabot, Martin St-Jean, Danielle E. Walker, Eric C. LaCasse, David F. Stojdl, Robert G. Korneluk and Martin Holcik _

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Oncotarget. 2017; 8:3495-3508. https://doi.org/10.18632/oncotarget.13849

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Abstract

Christine C. Dobson1,2, Thet Naing1, Shawn T. Beug1, Mame D. Faye1, Janelle Chabot1, Martin St-Jean1, Danielle E. Walker1, Eric C. LaCasse1, David F. Stojdl1,3, Robert G. Korneluk1,3, Martin Holcik1,4

1Molecular Biomedicine Program, Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada

2Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada

4Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada

Correspondence to:

Martin Holcik, email: [email protected]

Keywords: rhabdomyosarcoma, Smac mimetic, oncolytic virus, immunotherapy

Received: June 20, 2016    Accepted: November 23, 2016    Published: December 10, 2016

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.


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