The Oncolytic Activity of Myxoma Virus against Soft Tissue Sarcoma Is Mediated by the Overexpression of Ribonucleotide Reductase

Yanghee Woo, Susanne G. Warner, Rula Geha, Marianne M. Stanford, Penelope Decarolis, Masmudur M. Rahman, Samuel Singer, Grant McFadden, Yuman Fong

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Myxoma virus (MYXV) is an oncolytic poxvirus that lacks the gene for 1 of the subunits of ribonucleotide reductase (RR), a crucial DNA synthesis and repair enzyme. The overexpression of RR has been implicated in the invasiveness of several cancers, including soft tissue sarcomas (STS). The purpose of the study was to investigate the oncolytic efficacy of MYXV in STS with different levels of RR expression. Methods: The oncolytic effect of recombinant MYXV was evaluated in 4 human STS cell lines, LS141 (a dedifferentiated liposarcoma), DDLS8817 (a dedifferentiated liposarcoma), RDD2213 (recurrent dedifferentiated liposarcoma), and HSSYII (a synovial sarcoma) using infectivity and cytotoxicity assays. Following the overexpression of RRM2 by cDNA transfection and silencing of RRM2 by siRRM2 in these STS cell lines, the RRM2 expression levels were analyzed by Western blot. Results: We observed a direct correlation between viral oncolysis and RRM2 mRNA levels (R = 0.96) in STS. Higher RRM2 expression was associated with a more robust cell kill. Silencing the RRM2 gene led to significantly greater cell survival (80%) compared with the control group (P =.003), whereas overexpression of the RRM2 increased viral oncolysis by 33% (P <.001). Conclusions: Our results show that the oncolytic effects of MYXV correlate directly with RR expression levels and are enhanced in STS cell lines with naturally occurring or artificially induced high expression levels of RR. Myxoma virus holds promise in the treatment of advanced soft tissue cancer, especially in tumors overexpressing RR.

Original languageEnglish (US)
JournalClinical Medicine Insights: Oncology
Volume15
DOIs
StatePublished - 2021

Keywords

  • Soft tissue sarcoma
  • biomarker
  • myxoma virus
  • oncolytic viral therapy
  • ribonucleotide reductase

ASJC Scopus subject areas

  • Oncology

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