Gampala, SilpaShah, FenilZhang, ChiRhodes, Steven D.Babb, OliviaGrimard, MichelleWireman, Randall S.Rad, EllieCalver, BrianBai, Ren-YuanStaedtke, VerenaHulsey, Emily L.Saadatzadeh, M. RezaPollok, Karen E.Tong, YanSmith, Abbi E.Clapp, D. WadeTee, Andrew R.Kelley, Mark R.Fishel, Melissa L.2024-08-082024-08-082021Gampala S, Shah F, Zhang C, et al. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours [published correction appears in Br J Cancer. 2022 Oct;127(7):1378-1379. doi: 10.1038/s41416-022-01938-9]. Br J Cancer. 2021;124(9):1566-1580. doi:10.1038/s41416-021-01270-8https://hdl.handle.net/1805/42700Background: 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.en-USAttribution 4.0 InternationalTumor biomarkersNeurofibrosarcomaSTAT3 transcription factorArticle