Enhancer of zeste homolog 2 (EZH2) inhibitors

被引：152

作者：

Gulati, Nitya ^{[1
,2
]}

Beguelin, Wendy ^{[3
]}

Giulino-Roth, Lisa ^{[1
,2
,3
]}

机构：

[1] Weill Cornell Med Coll, Div Pediat Hematol Oncol, Dept Pediat, New York, NY USA

[2] Mem Sloan Kettering Canc Ctr, Div Pediat Hematol Oncol, 1275 York Ave, New York, NY 10021 USA

[3] Weill Cornell Med Coll, Div Hematol Oncol, Dept Med, New York, NY USA

来源：

LEUKEMIA & LYMPHOMA | 2018年 / 59卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Epigenetic; non-Hodgkin lymphoma; EZH2; inhibitors; B-CELL LYMPHOMAS; HISTONE METHYLTRANSFERASE EZH2; GERMINAL CENTER FORMATION; REPRESSIVE COMPLEX 2; NON-HODGKIN-LYMPHOMA; SELECTIVE-INHIBITION; CANCER EPIGENETICS; POLYCOMB; POTENT; MUTATIONS;

D O I：

10.1080/10428194.2018.1430795

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Dysregulation of the histone methyltransferase EZH2 plays a critical role in the development of a variety of malignancies including B-cell lymphomas. As a result, a series of small molecule inhibitors of EZH2 have been developed and studied in the pre-clinical setting. Three EZH2 inhibitors: tazemetostat (EPZ-6438), GSK2816126 and CPI-1205 have moved into phase I/phase II clinical trials in patients with non-Hodgkin lymphoma and genetically defined solid tumors. Early data from the tazemetostat trials indicate an acceptable safety profile and early signs of activity in diffuse large B-cell lymphoma and follicular lymphoma, including patients with EZH2 wild-type and mutant tumors. In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.

引用

页码：1574 / 1585

页数：12

共 77 条

[1] Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling [J].

Alizadeh, AA ;

Eisen, MB ;

Davis, RE ;

Ma, C ;

Lossos, IS ;

Rosenwald, A ;

Boldrick, JG ;

Sabet, H ;

Tran, T ;

Yu, X ;

Powell, JI ;

Yang, LM ;

Marti, GE ;

Moore, T ;

Hudson, J ;

Lu, LS ;

Lewis, DB ;

Tibshirani, R ;

Sherlock, G ;

Chan, WC ;

Greiner, TC ;

Weisenburger, DD ;

Armitage, JO ;

Warnke, R ;

Levy, R ;

Wilson, W ;

Grever, MR ;

Byrd, JC ;

Botstein, D ;

Brown, PO ;

Staudt, LM .

NATURE, 2000, 403 (6769) :503-511

[2]

[Anonymous], 2015, BLOOD

[3]

[Anonymous], HEMATOL ONCOL SS1

[4] Epigenetic protein families: a new frontier for drug discovery [J].

Arrowsmith, Cheryl H. ;

Bountra, Chas ;

Fish, Paul V. ;

Lee, Kevin ;

Schapira, Matthieu .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (05) :384-400

[5] Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors [J].

Baker, Theresa ;

Nerle, Sujata ;

Pritchard, Justin ;

Zhao, Boyang ;

Rivera, Victor M. ;

Garner, Andrew ;

Gonzalvez, Francois .

ONCOTARGET, 2015, 6 (32) :32646-32655

[6] EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop [J].

Beguelin, Wendy ;

Rivas, Martin A. ;

Fernandez, Maria T. Calvo ;

Teater, Matt ;

Purwada, Alberto ;

Redmond, David ;

Shen, Hao ;

Challman, Matt F. ;

Elemento, Olivier ;

Singh, Ankur ;

Melnick, Ari M. .

NATURE COMMUNICATIONS, 2017, 8

[7] EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis [J].

Beguelin, Wendy ;

Teater, Matt ;

Gearhart, Micah D. ;

Fernandez, Maria Teresa Calvo ;

Goldstein, Rebecca L. ;

Cardenas, Mariano G. ;

Hatzi, Katerina ;

Rosen, Monica ;

Shen, Hao ;

Corcoran, Connie M. ;

Hamline, Michelle Y. ;

Gascoyne, Randy D. ;

Levine, Ross L. ;

Abdel-Wahab, Omar ;

Licht, Jonathan D. ;

Shaknovich, Rita ;

Elemento, Olivier ;

Bardwell, Vivian J. ;

Melnick, Ari M. .

CANCER CELL, 2016, 30 (02) :197-213

[8] EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation [J].

Beguelin, Wendy ;

Popovic, Relja ;

Teater, Matt ;

Jiang, Yanwen ;

Bunting, Karen L. ;

Rosen, Monica ;

Shen, Hao ;

Yang, Shao Ning ;

Wang, Ling ;

Ezponda, Teresa ;

Martinez-Garcia, Eva ;

Zhang, Haikuo ;

Zheng, Yupeng ;

Verma, Sharad K. ;

McCabe, Michael T. ;

Ott, Heidi M. ;

Van Aller, Glenn S. ;

Kruger, Ryan G. ;

Liu, Yan ;

McHugh, Charles F. ;

Scott, David W. ;

Chung, Young Rock ;

Kelleher, Neil ;

Shaknovich, Rita ;

Creasy, Caretha L. ;

Gascoyne, Randy D. ;

Wong, Kwok-Kin ;

Cerchietti, Leandro ;

Levine, Ross L. ;

Abdel-Wahab, Omar ;

Licht, Jonathan D. ;

Elemento, Olivier ;

Melnick, Ari M. .

CANCER CELL, 2013, 23 (05) :677-692

[9]

Blakemore SJ, 2017, HEMATOL ONCOL, V35, P159

[10] EZH2 mutations are frequent and represent an early event in follicular lymphoma [J].

Boedoer, Csaba ;

Grossmann, Vera ;

Popov, Nikolay ;

Okosun, Jessica ;

O'Riain, Ciaran ;

Tan, King ;

Marzec, Jacek ;

Araf, Shamzah ;

Wang, Jun ;

Lee, Abigail M. ;

Clear, Andrew ;

Montoto, Silvia ;

Matthews, Janet ;

Iqbal, Sameena ;

Rajnai, Hajnalka ;

Rosenwald, Andreas ;

Ott, German ;

Campo, Elias ;

Rimsza, Lisa M. ;

Smeland, Erlend B. ;

Chan, Wing C. ;

Braziel, Rita M. ;

Staudt, Louis M. ;

Wright, George ;

Lister, T. Andrew ;

Elemento, Olivier ;

Hills, Robert ;

Gribben, John G. ;

Chelala, Claude ;

Matolcsy, Andras ;

Kohlmann, Alexander ;

Haferlach, Torsten ;

Gascoyne, Randy D. ;

Fitzgibbon, Jude .

BLOOD, 2013, 122 (18) :3165-3168

← 1 2 3 4 5 6 7 8 →