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

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.

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

“…Together, our gene expression findings indicate that APE1 coordinates and is involved in most of the steps of BER; alterations in its cellular level impact other important genes in the BER pathway [ 36 ]. This contrasts with what has been observed in cancer studies [ 24 , 37 ].…”

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

“…APE1/Ref-1′s role in DNA repair, RNA quality control, miRNA metabolism and redox activation of transcription factors NF-κB, HIF-1α, STAT3, AP-1 and p53 has suggested that it may be a therapeutic target for many cancers [ 15 , 17 , 64 ]. Increased expression of APE1/Ref-1 is associated with cancer progression, angiogenesis and resistance to therapy in many cancers, including cancers of the pancreas, bladder, colon, prostate, lung, breast, liver, ovary, bone, malignant peripheral nerve-sheath tumors (MPNST), sarcomas and many more [ 15 , 17 , 26 , 36 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Pharmacologically inhibiting the redox function of APE1/Ref-1 may be beneficial for the treatment of various cancers, as the inhibition of APE1/Ref-1 has been associated with enhanced colorectal cancer tumor regression in preclinical studies and enhanced promyelocytic leukemia response to treatment [ 15 , 38 , 64 ].…”

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

“…Inhibitors of DNA repair proteins have widely been studied alone or in conjunction with radiotherapy to enhance tumor suppression. For instance, the inhibition of the DNA base excision repair (BER) protein apurinic/apyrimidinic endonuclease, APE1, has been shown to suppress growth of several cancers ( 33 , 34 ). Similarly, overexpression of APE1 has been linked to radioresistance ( 35 , 36 ), and suppression has been shown to enhance cancer cells to RT ( 37 ).…”