Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA.
Neoplasia. 2011 Feb;13(2):145-53. doi: 10.1593/neo.101202.
ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P = .001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted.
依维莫司（trabectedin；Yondelis）在欧洲被批准用于软组织肉瘤的治疗。初步和 2 期临床试验结果表明，依维莫司在黏液样脂肪肉瘤中具有较高的缓解率，这在一定程度上归因于其对 FUS-CHOP 转录因子的抑制作用。在本报告中，我们发现依维莫司对特定致癌转录因子的调节作用可能扩展到其他肿瘤类型。我们证明，在一组儿科肉瘤中，携带 EWS-FLI1 转录因子的尤文肉瘤家族肿瘤（ESFTs）细胞系对依维莫司的敏感性最高，与骨肉瘤、横纹肌肉瘤和滑膜肉瘤相比。我们发现，依维莫司可逆转两种不同 ESFT 细胞系中 EWS-FLI1 诱导的下游靶基因的基因特征（P=0.001）。此外，依维莫司直接抑制已知的 EWS-FLI1 下游靶基因 NR0B1 荧光素酶报告基因构建体的启动子活性，而不改变 ESFT 细胞中组成型激活对照的活性。此外，这种作用是特异性的，因为 EWS-FLI1 的强制表达在通常缺乏这种融合蛋白的细胞类型 HT1080 中诱导相同的 NR0B1 启动子，但这种激活可被依维莫司完全阻断。最后，我们使用基因集富集分析来确认依维莫司在 ESFT 细胞中的其他作用机制。这些结果表明，依维莫司在治疗易位阳性肿瘤方面具有特殊作用。此外，EWS-FLI1 的调节使其成为 ESFT 的新型靶向药物，并表明进一步开发该化合物治疗 ESFT 是合理的。
