Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University, School of Medicine, Indianapolis, IN, USA.
Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, USA.
Br J Cancer. 2021 Apr;124(9):1566-1580. doi: 10.1038/s41416-021-01270-8. Epub 2021 Mar 3.
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.
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.
MPNSTs from Nf1-ArfPostnCre 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.
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.
MPNST 是一种罕见的软组织肉瘤，可发生于 NF1 患者。现有的化疗药物和靶向药物在 MPNST 的治疗中均不成功，最近的研究结果表明 STAT3 和 HIF1-α在驱动 MPNST 中起作用。STAT3 和 HIF1-α 的 DNA 结合和转录活性均受 Redox 因子-1（Ref-1）氧化还原功能的调节。第一代 Ref-1 抑制剂 APX3330 正在进行癌症临床试验，可应用于 MPNST。
我们对各种 MPNST 模型中的 Ref-1 和 p-STAT3 表达进行了特征描述。用抑制剂处理后，通过 qPCR 和 Western blot 测量肿瘤生长以及凋亡和信号通路的生物标志物。
当恶性转化发生时，Nf1-ArfPostnCre 小鼠的 MPNST 表现出显著增加的 p-STAT3 和 Ref-1 表达阳性。抑制 Ref-1 或 STAT3 可在体外和体内损害 MPNST 的生长并诱导凋亡。抑制 Ref-1 或 STAT3 后，MPNST 患者中高表达的基因下调。抑制 Ref-1 或 STAT3 后，Ref-1 或 STAT3 下游的几个生物标志物也下调。
我们的研究结果表明，使用新型首创的小分子针对肉瘤中的重要 MPNST 信号节点是一种独特的治疗方法，有可能转化为临床应用。
