超级增强子:肿瘤治疗的新靶点

doi:10.3969/j.issn.1004-583X.2023.03.015

摘要/Abstract

摘要：

超级增强子(super-enhancers,SEs)可以通过调控靶基因的转录,从而在肿瘤发生发展中发挥关键作用。靶向抑制SEs的活性或敲除SEs片段可能成为肿瘤治疗的新方法。本文主要综述了SEs在肿瘤中的作用以及以SEs为靶点的抗肿瘤小分子抑制剂相关研究及临床试验。旨在为研发新的抗肿瘤药物提供理论依据。

关键词: 肿瘤, 超级增强子, BET, CDKs, 小分子抑制剂

中图分类号:

R730.54

彭灵智, 祝成楼, 刘天祥. 超级增强子:肿瘤治疗的新靶点[J]. 临床荟萃, 2023, 38(3): 273-278.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2023.03.015

https://huicui.hebmu.edu.cn/CN/Y2023/V38/I3/273

图/表 2

参考文献 65

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抑制剂	靶点	肿瘤
JQ1	BRD4	前列腺癌^[24],乳腺癌^[25],结肠癌^[26]等
I-BET151	BRD4	急性髓性白血病^[27],多形性胶质母细胞瘤^[28],多发性骨髓瘤^[29]等
BETd-246	BRD2,BRD3,BRD4	三阴性乳腺癌^[30],默克尔细胞癌^[31],乳腺癌^[32]等
GS-5829	BRD2,BRD3,BRD4	慢性淋巴细胞性白血病^[33],子宫浆液性癌^[34]等
INCB057643	BRD2,BRD3,BRD4	胰腺癌^[35],弥漫大B细胞淋巴瘤^[36],前列腺癌^[37]等
INCB054329	BRD2,BRD3,BRD4	卵巢癌^[38],前列腺癌^[39],急性髓系白血病^[40]等
THZ1	CDK7	卵巢癌^[41],鼻咽癌^[42],膀胱癌^[43],小细胞肺癌^[44]等
THZ2	CDK7	骨肉瘤^[45],胃癌^[46]等
SY-1365	CDK7	卵巢癌和乳腺癌^[47]等
THZ531	CDK12,CDK13	前列腺癌^[48],急性T细胞淋巴瘤^[49],甲状腺未分化癌^[50]等
Lee011	CDK4, CDK6	乳腺癌^[51],黑色素瘤^[51],神经母细胞瘤^[51],尤因肉瘤^[52]等
GZ17-6.02	-	胰腺导管腺癌^[53],恶性胶质瘤^[54]等
SY-1425	RARα	急性髓性白血病^[55]等

抑制剂	靶点	肿瘤
JQ1	BRD4	前列腺癌^[24],乳腺癌^[25],结肠癌^[26]等
I-BET151	BRD4	急性髓性白血病^[27],多形性胶质母细胞瘤^[28],多发性骨髓瘤^[29]等
BETd-246	BRD2,BRD3,BRD4	三阴性乳腺癌^[30],默克尔细胞癌^[31],乳腺癌^[32]等
GS-5829	BRD2,BRD3,BRD4	慢性淋巴细胞性白血病^[33],子宫浆液性癌^[34]等
INCB057643	BRD2,BRD3,BRD4	胰腺癌^[35],弥漫大B细胞淋巴瘤^[36],前列腺癌^[37]等
INCB054329	BRD2,BRD3,BRD4	卵巢癌^[38],前列腺癌^[39],急性髓系白血病^[40]等
THZ1	CDK7	卵巢癌^[41],鼻咽癌^[42],膀胱癌^[43],小细胞肺癌^[44]等
THZ2	CDK7	骨肉瘤^[45],胃癌^[46]等
SY-1365	CDK7	卵巢癌和乳腺癌^[47]等
THZ531	CDK12,CDK13	前列腺癌^[48],急性T细胞淋巴瘤^[49],甲状腺未分化癌^[50]等
Lee011	CDK4, CDK6	乳腺癌^[51],黑色素瘤^[51],神经母细胞瘤^[51],尤因肉瘤^[52]等
GZ17-6.02	-	胰腺导管腺癌^[53],恶性胶质瘤^[54]等
SY-1425	RARα	急性髓性白血病^[55]等

抑制剂	靶点	肿瘤	临床试验
OTX-015	BRD2, BRD3, BRD4	急性髓系白血病,弥漫大B细胞淋巴瘤,急性淋巴细胞白血病,多发性骨髓瘤	Ⅰ/Ⅱ期,NCT02303782,撤销
		急性髓系白血病	Ⅰ/Ⅱ期,NCT02303782,撤销
		多形性胶质母细胞瘤	Ⅱ期,NCT02296476,终止
		NUT中线癌,三阴性乳腺癌,非小细胞肺癌,去势抵抗性前列腺癌	Ⅰ期,NCT02698176,终止
		NUT中线癌,三阴性乳腺癌,非小细胞肺癌,去势抵抗性前列腺癌,胰腺导管腺癌	Ⅰ期,NCT02259114,完成
		急性髓性白血病,弥漫大B细胞淋巴瘤	Ⅰ期,NCT02698189,终止
CPI-0610	BRD4	周围神经肿瘤	Ⅱ期,NCT02986919,撤销
		多发性骨髓瘤	Ⅱ期,NCT04603495,招募
		多发性骨髓瘤	Ⅰ期,NCT02157636,完成
		淋巴瘤	Ⅰ期,NCT01949883,完成
I-BET762	BRD2, BRD3 BRD4	复发性或难治性血液系统恶性肿瘤	Ⅰ期,NCT01943851,完成
		激素受体阳性(HR+)/人表皮生长因子受体2阴性(HER2-)晚期或转移性乳腺癌	Ⅱ期,NCT02964507,完成
	实体瘤	Ⅱ期,NCT03266159,撤销
		去势抵抗性前列腺癌	Ⅱ期,NCT03150056,招募
		NUT中线癌、小细胞肺癌、非小细胞肺癌、结直肠癌、神经母细胞瘤、去势抵抗性前列腺癌、三阴性乳腺癌、雌激素受体阳性(ER阳性)乳腺癌、MYCN驱动的实体瘤	Ⅰ期,NCT01587703,完成
		晚期或难治性实体瘤或淋巴瘤	Ⅰ期,NCT03925428,撤销
		转移性或不可切除性NUT中线癌	Ⅰ/Ⅱ期,NCT04116359,撤销
		NUT中线癌	NCT03702036,已失效
TEN-010	BRD2, BRD3 BRD4	NUT中线癌,弥漫大B细胞淋巴瘤	Ⅰ期,NCT01987362,完成
		急性髓系白血病,骨髓增生异常综合征	Ⅰ期,NCT02308761,完成
		弥漫大B细胞淋巴瘤,高级别B细胞淋巴瘤	Ⅰ期,NCT03255096,完成
GS-5829	BRD2,BRD3,BRD4	晚期实体瘤,淋巴瘤	Ⅰ期,NCT02392611,完成
		晚期雌激素受体阳性HER2阴性乳腺癌	Ⅰ/Ⅱ期,NCT02983604,终止
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT02607228,终止
ODM207	BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT0303559,完成
INCB057643	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT02711137,终止
		晚期实体瘤	Ⅰ/Ⅱ期,NCT02959437,完成
INCB054329	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT02431260,终止
BMS-986158	BRD2,BRD3,BRD4	小儿实体肿瘤,淋巴瘤,小儿脑瘤	Ⅰ期,NCT03936465,招募
		晚期肿瘤	Ⅰ/Ⅱ期,NCT02419417,招募
ZEN003694	BRD2,BRD3,BRD4	转移性去势抵抗性前列腺癌	Ⅰ期,NCT04986423,招募
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT04145375,招募
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT02711956,完成
		转移性去势抵抗性前列腺癌	Ⅰ期,NCT02705469,完成
		复发性卵巢、输卵管癌或原发性腹膜癌	Ⅱ期,NCT05071937,未招募
		三阴性乳腺癌	Ⅱ期,NCT03901469,未招募
		晚期和难治性实体肿瘤和淋巴瘤	Ⅰ/Ⅱ期,NCT05053971,未招募
		转移性或复发性恶性实体瘤,复发性铂耐药卵巢癌,难治性卵巢癌	Ⅰ期, NCT04840589,招募
		进展期/转移性/不可切除的NUT中线癌	Ⅰ/Ⅱ期,NCT05019716,未招募
		去势抵抗性前列腺癌/转移性前列腺癌/转移性前列腺小细胞癌	Ⅱ期,NCT04471974,招募
PLX2853	PLX2853	妇科恶性肿瘤,卵巢恶性肿瘤	Ⅰ/Ⅱ期,NCT04493619,招募
		小细胞肺癌,葡萄膜黑色素瘤,卵巢透明细胞癌,非霍奇金淋巴瘤,晚期恶性肿瘤,实体瘤,弥漫性大B细胞淋巴瘤,滤泡淋巴瘤	Ⅰ/Ⅱ期,NCT03297424,完成
		复发性或难治性急性髓性白血病(AML),骨髓增生异常综合征(MDS)	Ⅱ期,NCT03787498,完成
		转移性去势性前列腺癌	Ⅰ期,NCT04556617,完成
BI 894999	BRD4	晚期恶性肿瘤,NUT中线癌	Ⅰ期,NCT02516553,完成
GSK2820151	BRD2,BRD3,BRD4	复发或晚期实体瘤	Ⅰ期,NCT02630251,终止
BAY 1238097	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ期,NCT02369029,终止
SY-1365	CDK7	晚期实体瘤,乳腺癌,卵巢癌	Ⅰ期,NCT03134638,终止
THZ531	CDK12,CDK13	卵巢癌	肿瘤活检,NCT04555473,招募
Lee011	CDK4, CDK6	晚期实体瘤,巨块型肿瘤	Ⅰ期,NCT02934568,招募
		晚期实体肿瘤,转移性激素受体阳性乳腺癌	Ⅰ/Ⅰb期,NCT03775525,招募
SY-1425	RARα	急性髓系白血病,骨髓增生异常综合征	Ⅱ期,NCT02807558,未招募

抑制剂	靶点	肿瘤	临床试验
OTX-015	BRD2, BRD3, BRD4	急性髓系白血病,弥漫大B细胞淋巴瘤,急性淋巴细胞白血病,多发性骨髓瘤	Ⅰ/Ⅱ期,NCT02303782,撤销
		急性髓系白血病	Ⅰ/Ⅱ期,NCT02303782,撤销
		多形性胶质母细胞瘤	Ⅱ期,NCT02296476,终止
		NUT中线癌,三阴性乳腺癌,非小细胞肺癌,去势抵抗性前列腺癌	Ⅰ期,NCT02698176,终止
		NUT中线癌,三阴性乳腺癌,非小细胞肺癌,去势抵抗性前列腺癌,胰腺导管腺癌	Ⅰ期,NCT02259114,完成
		急性髓性白血病,弥漫大B细胞淋巴瘤	Ⅰ期,NCT02698189,终止
CPI-0610	BRD4	周围神经肿瘤	Ⅱ期,NCT02986919,撤销
		多发性骨髓瘤	Ⅱ期,NCT04603495,招募
		多发性骨髓瘤	Ⅰ期,NCT02157636,完成
		淋巴瘤	Ⅰ期,NCT01949883,完成
I-BET762	BRD2, BRD3 BRD4	复发性或难治性血液系统恶性肿瘤	Ⅰ期,NCT01943851,完成
		激素受体阳性(HR+)/人表皮生长因子受体2阴性(HER2-)晚期或转移性乳腺癌	Ⅱ期,NCT02964507,完成
	实体瘤	Ⅱ期,NCT03266159,撤销
		去势抵抗性前列腺癌	Ⅱ期,NCT03150056,招募
		NUT中线癌、小细胞肺癌、非小细胞肺癌、结直肠癌、神经母细胞瘤、去势抵抗性前列腺癌、三阴性乳腺癌、雌激素受体阳性(ER阳性)乳腺癌、MYCN驱动的实体瘤	Ⅰ期,NCT01587703,完成
		晚期或难治性实体瘤或淋巴瘤	Ⅰ期,NCT03925428,撤销
		转移性或不可切除性NUT中线癌	Ⅰ/Ⅱ期,NCT04116359,撤销
		NUT中线癌	NCT03702036,已失效
TEN-010	BRD2, BRD3 BRD4	NUT中线癌,弥漫大B细胞淋巴瘤	Ⅰ期,NCT01987362,完成
		急性髓系白血病,骨髓增生异常综合征	Ⅰ期,NCT02308761,完成
		弥漫大B细胞淋巴瘤,高级别B细胞淋巴瘤	Ⅰ期,NCT03255096,完成
GS-5829	BRD2,BRD3,BRD4	晚期实体瘤,淋巴瘤	Ⅰ期,NCT02392611,完成
		晚期雌激素受体阳性HER2阴性乳腺癌	Ⅰ/Ⅱ期,NCT02983604,终止
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT02607228,终止
ODM207	BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT0303559,完成
INCB057643	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT02711137,终止
		晚期实体瘤	Ⅰ/Ⅱ期,NCT02959437,完成
INCB054329	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ/Ⅱ期,NCT02431260,终止
BMS-986158	BRD2,BRD3,BRD4	小儿实体肿瘤,淋巴瘤,小儿脑瘤	Ⅰ期,NCT03936465,招募
		晚期肿瘤	Ⅰ/Ⅱ期,NCT02419417,招募
ZEN003694	BRD2,BRD3,BRD4	转移性去势抵抗性前列腺癌	Ⅰ期,NCT04986423,招募
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT04145375,招募
		转移性去势抵抗性前列腺癌	Ⅰ/Ⅱ期,NCT02711956,完成
		转移性去势抵抗性前列腺癌	Ⅰ期,NCT02705469,完成
		复发性卵巢、输卵管癌或原发性腹膜癌	Ⅱ期,NCT05071937,未招募
		三阴性乳腺癌	Ⅱ期,NCT03901469,未招募
		晚期和难治性实体肿瘤和淋巴瘤	Ⅰ/Ⅱ期,NCT05053971,未招募
		转移性或复发性恶性实体瘤,复发性铂耐药卵巢癌,难治性卵巢癌	Ⅰ期, NCT04840589,招募
		进展期/转移性/不可切除的NUT中线癌	Ⅰ/Ⅱ期,NCT05019716,未招募
		去势抵抗性前列腺癌/转移性前列腺癌/转移性前列腺小细胞癌	Ⅱ期,NCT04471974,招募
PLX2853	PLX2853	妇科恶性肿瘤,卵巢恶性肿瘤	Ⅰ/Ⅱ期,NCT04493619,招募
		小细胞肺癌,葡萄膜黑色素瘤,卵巢透明细胞癌,非霍奇金淋巴瘤,晚期恶性肿瘤,实体瘤,弥漫性大B细胞淋巴瘤,滤泡淋巴瘤	Ⅰ/Ⅱ期,NCT03297424,完成
		复发性或难治性急性髓性白血病(AML),骨髓增生异常综合征(MDS)	Ⅱ期,NCT03787498,完成
		转移性去势性前列腺癌	Ⅰ期,NCT04556617,完成
BI 894999	BRD4	晚期恶性肿瘤,NUT中线癌	Ⅰ期,NCT02516553,完成
GSK2820151	BRD2,BRD3,BRD4	复发或晚期实体瘤	Ⅰ期,NCT02630251,终止
BAY 1238097	BRD2,BRD3,BRD4	晚期实体瘤	Ⅰ期,NCT02369029,终止
SY-1365	CDK7	晚期实体瘤,乳腺癌,卵巢癌	Ⅰ期,NCT03134638,终止
THZ531	CDK12,CDK13	卵巢癌	肿瘤活检,NCT04555473,招募
Lee011	CDK4, CDK6	晚期实体瘤,巨块型肿瘤	Ⅰ期,NCT02934568,招募
		晚期实体肿瘤,转移性激素受体阳性乳腺癌	Ⅰ/Ⅰb期,NCT03775525,招募
SY-1425	RARα	急性髓系白血病,骨髓增生异常综合征	Ⅱ期,NCT02807558,未招募

超级增强子:肿瘤治疗的新靶点

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