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

Gampala, Silpa, Shah, Fenil, Zhang, Chi, Rhodes, Steven D., Babb, Olivia, Grimard, Michelle, Wireman, Randall S., Rad, Ellie, Calver, Brian, Bai, Ren-Yuan, Staedtke, Verena, Hulsey, Emily L., Saadatzadeh, M. Reza, Pollok, Karen E., Tong, Yan, Smith, Abbi E., Clapp, D. Wade, Tee, Andrew R., Kelley, Mark R. and Fishel, Melissa L. 2021. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British Journal of Cancer 124 (9) , 1566–1580. 10.1038/s41416-021-01270-8

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0007-0920
Date of First Compliant Deposit:	27 August 2021
Date of Acceptance:	5 January 2021
Last Modified:	30 May 2022 07:38
URI:	https://orca.cardiff.ac.uk/id/eprint/143731

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