Theisen Emily R, Pishas Kathleen I, Saund Ranajeet S, Lessnick Stephen L
Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
Cancer Therapeutics Laboratory, Centre for Personalized Cancer Medicine, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Oncotarget. 2016 Apr 5;7(14):17616-30. doi: 10.18632/oncotarget.7124.
Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma. However, transcription factors are notoriously difficult targets for the development of small molecules. Improved understanding of the oncogenic mechanisms employed by EWS-FLI to hijack normal cellular programming has uncovered potential novel approaches to pharmacologically block EWS-FLI function. In this review we examine targeting the chromatin regulatory enzymes recruited to conspire in oncogenesis with a focus on the histone lysine specific demethylase 1 (LSD1). LSD1 inhibitors are being aggressively investigated in acute myeloid leukemia and the results of early clinical trials will help inform the future use of LSD1 inhibitors in sarcoma. High LSD1 expression is observed in Ewing sarcoma patient samples and mechanistic and preclinical data suggest LSD1 inhibition globally disrupts the function of EWS-ETS proteins.
尤因肉瘤是一种侵袭性原发性儿童骨肿瘤，常诊断于青少年和年轻成年人。一种具有诊断意义的相互染色体易位导致一个融合基因，该基因编码的蛋白质其N端来自FUS/EWS/TAF15（FET）蛋白家族成员，通常是EWS，C端包含ETS转录因子的DNA结合结构域，通常是FLI1。近85%的病例表达EWS-FLI蛋白，该蛋白作为转录因子发挥作用并驱动肿瘤发生。作为主要的基因组病变以及在正常细胞中不表达的蛋白质，破坏EWS-FLI功能是尤因肉瘤一种有吸引力的治疗策略。然而，转录因子是出了名的难以成为小分子开发的靶点。对EWS-FLI用于劫持正常细胞程序的致癌机制的深入了解揭示了药理学阻断EWS-FLI功能的潜在新方法。在本综述中，我们研究靶向那些被招募来共同参与肿瘤发生的染色质调节酶，重点关注组蛋白赖氨酸特异性去甲基化酶1（LSD1）。LSD1抑制剂正在急性髓系白血病中进行积极研究，早期临床试验结果将有助于指导LSD1抑制剂未来在肉瘤中的应用。在尤因肉瘤患者样本中观察到LSD1高表达，机制和临床前数据表明LSD1抑制会全面破坏EWS-ETS蛋白的功能。
