Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
Year: 2021
Type: article
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: 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.
Source: British Journal of Cancer
Authors: 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
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Awards: (PQ9)Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathy, G1628476732, Thrombin-dependent mechanisms of pancreatic ductal adenocarcinoma disease, G2098044338, Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis, (PQ12) Enhancement of DNA repair in neurons via a targeted APE1 small molecule modifier to decrease and reverse chemotherapy-induced peripheral neuropathy (CIPN), G3631430387, G394632119, G4119534169, G4616508932, Hyperglycemia mediated myeloproliferative disease, G5611974873, G5850682332, G6237288963, G6447529026, G6813337281, G7321284031, G9000025480, G9000212862, G9000279830, Developmental and Hyperactive Ras Tumor (DHART) SPORE
OpenAlex ID: W3135590355