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Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma
Journal article   Open access

Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma

Michael P. Phelps, Heechang Yang, Shivani Patel, Masmudur M. Rahman, Grant McFadden and Eleanor Chen
Molecular therapy. Oncolytics, Vol.11, pp.52-61
12/21/2018
DOI: https://doi.org/10.1016/j.omto.2018.09.001
PMID: 30364635
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Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma3.15 MBDownloadView
Open Access CC BY-NC-ND V4.0
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https://doi.org/10.1016/j.omto.2018.09.001View
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Abstract

Life Sciences & Biomedicine Medicine, Research & Experimental Research & Experimental Medicine Oncology
Aberrant activation of the receptor tyrosine kinase-mediated RAS signaling cascade is the primary driver of embryonal rhabdomyosarcoma (ERMS), a pediatric cancer characterized by a block in myogenic differentiation. To investigate the cellular function of activated RAS signaling in regulating the growth and differentiation of ERMS cells, we genetically ablated activated RAS oncogenes with high-efficiency genome-editing technology. Knockout of NRAS in CRISPR-inducible ERMS xenograft models resulted in near-complete tumor regression through a combination of cell death and myogenic differentiation. Utilizing this strategy for therapeutic RAS targeting in ERMS, we developed a recombinant oncolytic myxoma virus (MYXV) engineered with CRISPR/Cas9 gene-editing capability. Treatment of pre-clinical human ERMS tumor xenografts with an NRAS-targeting version of this MYXV significantly reduced tumor growth and increased overall survival. Our data suggest that targeted gene-editing cancer therapies have promising translational applications, especially with improvements to gene-targeting specificity and oncolytic vector technology.

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