Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma

Michael P. Phelps, Heechang Yang, Shivani Patel, Masmudur Rahman, Douglas McFadden, Eleanor Chen

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalMolecular Therapy - Oncolytics
Volume11
DOIs
StatePublished - Dec 21 2018

Keywords

  • cancer gene therapy
  • CRISPR
  • myxoma
  • oncolytic virus
  • RAS
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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