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 Citations (Scopus)

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

Fingerprint

Oncolytic Viruses
Embryonal Rhabdomyosarcoma
Rhabdomyosarcoma
Myxoma virus
Clustered Regularly Interspaced Short Palindromic Repeats
Neoplasms
Heterografts
Technology
Gene Targeting
Receptor Protein-Tyrosine Kinases
Growth
Oncogenes
Cell Death
Pediatrics
Survival
Therapeutics
Gene Editing

Keywords

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

ASJC Scopus subject areas

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

Cite this

Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma. / Phelps, Michael P.; Yang, Heechang; Patel, Shivani; Rahman, Masmudur; McFadden, Douglas; Chen, Eleanor.

In: Molecular Therapy - Oncolytics, Vol. 11, 21.12.2018, p. 52-61.

Research output: Contribution to journalArticle

Phelps, Michael P. ; Yang, Heechang ; Patel, Shivani ; Rahman, Masmudur ; McFadden, Douglas ; Chen, Eleanor. / Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma. In: Molecular Therapy - Oncolytics. 2018 ; Vol. 11. pp. 52-61.
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