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

• Published in: British journal of cancer Vol. 124; no. 9; pp. 1566 - 1580
• Main Authors: 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., Fishel, Melissa L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.04.2021; Nature Publishing Group
• Subjects: 631/67/1798; 631/67/2332; Adolescent; Animals; Apoptosis; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Proliferation; Chemotherapy; Clinical trials; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Medicine; Neurofibrosarcoma - genetics; Neurofibrosarcoma - metabolism; Neurofibrosarcoma - pathology; Oncology; Patients; Peripheral nerves; Prognosis; Redox factor-1; Sarcoma; Signal transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Therapeutic targets; Transcription; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-021-01270-8

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-Arf flox/flox PostnCre 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.