Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

Silpa Gampala, Fenil Shah, Chi Zhang, Steven D. Rhodes, Olivia Babb, Michelle Grimard, Randall S. Wireman, Ellie Rad, Brian Calver, Ren Yuan Bai, Verena Staedtke, Emily L. Hulsey, M. Reza Saadatzadeh, Karen E. Pollok, Yan Tong, Abbi E. Smith, D. Wade Clapp, Andrew R. Tee, Mark R. Kelley, Melissa L. Fishel

Research output: Contribution to journalArticlepeer-review


Background: MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) redox function. A first-generation Ref-1 inhibitor, APX3330, is being tested in cancer clinical trials and could be applied to MPNST. Methods: We characterised Ref-1 and p-STAT3 expression in various MPNST models. Tumour growth, as well as biomarkers of apoptosis and signalling pathways, were measured by qPCR and western blot following treatment with inhibitors of Ref-1 or STAT3. Results: MPNSTs from Nf1-Arfflox/floxPostnCre mice exhibit significantly increased positivity of p-STAT3 and Ref-1 expression when malignant transformation occurs. Inhibition of Ref-1 or STAT3 impairs MPNST growth in vitro and in vivo and induces apoptosis. Genes highly expressed in MPNST patients are downregulated following inhibition of Ref-1 or STAT3. Several biomarkers downstream of Ref-1 or STAT3 were also downregulated following Ref-1 or STAT3 inhibition. Conclusions: Our findings implicate a unique therapeutic approach to target important MPNST signalling nodes in sarcomas using new first-in-class small molecules for potential translation to the clinic.

Original languageEnglish (US)
Pages (from-to)1566-1580
Number of pages15
JournalBritish journal of cancer
Issue number9
StatePublished - Apr 27 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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