通过抑制 EZH2 靶向肉瘤中的表观遗传学。
Targeting epigenetics in sarcomas through EZH2 inhibition.
机构信息
Institut Bergonié, Early Phase Trial and Sarcoma Units, 229 cours de l'Argonne, 33076, Bordeaux, CEDEX, France.
INSERM U1218, Bordeaux, France.
出版信息
J Hematol Oncol. 2020 Apr 7;13(1):33. doi: 10.1186/s13045-020-00868-4.
Abstract
Soft-tissue sarcomas represent a heterogeneous group of diseases with distinct genetic and clinical features accounting for up to 1% of cancer in adults and 15% of cancer in children. Epithelioid sarcoma is an extremely rare and aggressive tumor affecting young adults that is characterized by loss of INI1 expression. INI1 (SMARCB1, SNF5, BAF47) is a subunit of the SWI/SNF chromatin remodeling complex that opposes the enzymatic function of EZH2. When INI1 loses its regulatory function, EZH2 activity is de-regulated, allowing EZH2 to play a driving, oncogenic role. Tazemetostat, a specific EZH2 inhibitor, has just been approved for patients with advanced epithelioid sarcoma and represents a new therapeutic option in this devastating disease.
摘要
软组织肉瘤是一组具有不同遗传和临床特征的异质性疾病，占成人癌症的 1%，儿童癌症的 15%。上皮样肉瘤是一种罕见且侵袭性很强的肿瘤，主要发生于年轻人，其特征是 INI1 表达缺失。INI1（SMARCB1、SNF5、BAF47）是 SWI/SNF 染色质重塑复合物的一个亚基，该复合物可拮抗 EZH2 的酶功能。当 INI1 失去其调节功能时，EZH2 活性就会失调，从而使 EZH2 发挥驱动致癌的作用。特异性 EZH2 抑制剂塔西美坦刚刚被批准用于治疗晚期上皮样肉瘤患者，为这一毁灭性疾病提供了新的治疗选择。
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2
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3
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Neuro Oncol. 2013 Feb;15(2):149-60. doi: 10.1093/neuonc/nos285. Epub 2012 Nov 28.
9
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Nat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084. Epub 2012 Sep 30.
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