现在治疗淋巴瘤容易多了。
Treating lymphoma is now a bit EZ-er.
机构信息
Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada; and.
Jewish General Hospital, McGill University, Montreal, QC, Canada.
出版信息
Blood Adv. 2021 Apr 27;5(8):2256-2263. doi: 10.1182/bloodadvances.2020002773.
Abstract
Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase, the first of a multitude of epigenetic regulators that have been identified as recurrently mutated in FL and germinal center diffuse large B-cell lymphoma. In this review, we discuss the initial discovery and ongoing exploration of the functional role of EZH2 mutations in lymphomagenesis. We also explore the path from the preclinical development of tazemetostat to its approval for the treatment of relapsed FL, and potential future therapeutic applications. We discuss the clinical data that led to the approval of tazemetostat and ongoing research into the function of EZH2 and of tazemetostat in lymphomas that derive from the germinal center, which could increase the applicability of this drug in the future.
摘要
他泽司他丁是首个获批用于治疗滤泡性淋巴瘤（FL）的表观遗传学疗法。它能抑制增强子结合锌指蛋白 2（EZH2）组蛋白甲基转移酶的活性，EZH2 是众多已被鉴定为在 FL 和生发中心弥漫性大 B 细胞淋巴瘤中频繁突变的表观遗传调控因子之一。在这篇综述中，我们讨论了 EZH2 突变在淋巴瘤发生中的最初发现和正在进行的功能作用研究。我们还探讨了从他泽司他丁的临床前开发到其获批用于治疗复发 FL 以及潜在未来治疗应用的过程。我们讨论了导致他泽司他丁获批的临床数据，以及正在进行的关于 EZH2 功能和他泽司他丁在生发中心起源的淋巴瘤中的作用的研究，这可能会增加该药物在未来的适用性。
相似文献
1
Treating lymphoma is now a bit EZ-er.现在治疗淋巴瘤容易多了。
Blood Adv. 2021 Apr 27;5(8):2256-2263. doi: 10.1182/bloodadvances.2020002773.
2
EZH2 inhibition by tazemetostat: mechanisms of action, safety and efficacy in relapsed/refractory follicular lymphoma.塔西美坦抑制 EZH2：在复发/难治性滤泡性淋巴瘤中的作用机制、安全性和疗效。
Future Oncol. 2021 Jun;17(17):2127-2140. doi: 10.2217/fon-2020-1244. Epub 2021 Mar 12.
3
Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan.在日本，对 EZH2 突变的复发性或难治性 B 细胞非霍奇金淋巴瘤进行 tazemetostat 的 II 期研究。
Cancer Sci. 2021 Sep;112(9):3627-3635. doi: 10.1111/cas.15040. Epub 2021 Jul 14.
4
Tazemetostat: a treatment option for relapsed/refractory follicular lymphoma.他替莫唑胺：复发/难治性滤泡性淋巴瘤的治疗选择。
Expert Opin Pharmacother. 2022 Feb;23(3):295-301. doi: 10.1080/14656566.2021.2014815. Epub 2021 Dec 14.
5
A Promising Future for Precision Epigenetic Therapy for Follicular and Diffuse Large B-Cell Lymphoma?精准表观遗传疗法治疗滤泡性和弥漫性大B细胞淋巴瘤的前景可期？
Blood Lymphat Cancer. 2022 Aug 4;12:99-106. doi: 10.2147/BLCTT.S282247. eCollection 2022.
6
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.生发中心来源的滤泡性和弥漫性大 B 细胞淋巴瘤中 EZH2（Tyr641）改变的体细胞突变。
Nat Genet. 2010 Feb;42(2):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17.
7
Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.塔西美替尼治疗复发或难治性滤泡性淋巴瘤患者的疗效：一项开放标签、单臂、多中心、2 期临床试验。
Lancet Oncol. 2020 Nov;21(11):1433-1442. doi: 10.1016/S1470-2045(20)30441-1. Epub 2020 Oct 6.
8
The role of tazemetostat in relapsed/refractory follicular lymphoma.他泽司他在复发/难治性滤泡性淋巴瘤中的作用。
Ther Adv Hematol. 2021 May 27;12:20406207211015882. doi: 10.1177/20406207211015882. eCollection 2021.
9
Emerging EZH2 Inhibitors and Their Application in Lymphoma.新型EZH2抑制剂及其在淋巴瘤中的应用
Curr Hematol Malig Rep. 2018 Oct;13(5):369-382. doi: 10.1007/s11899-018-0466-6.
10
Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma.在复发或难治性 B 细胞淋巴瘤的日本患者中开展的 tazemetostat 的 1 期研究。
Cancer Sci. 2021 Mar;112(3):1123-1131. doi: 10.1111/cas.14822. Epub 2021 Feb 15.
引用本文的文献
1
Pharmacological Advancements of PRC2 in Cancer Therapy: A Narrative Review.PRC2在癌症治疗中的药理学进展：一篇叙述性综述。
Life (Basel). 2024 Dec 11;14(12):1645. doi: 10.3390/life14121645.
2
Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion.靶向多梳沉默基因的合成读码器-致动器可阻断三阴性乳腺癌的增殖和侵袭。
GEN Biotechnol. 2023 Aug 1;2(4):301-316. doi: 10.1089/genbio.2023.0020. Epub 2023 Aug 17.
3
Aging and Age-Related Epigenetic Drift in the Pathogenesis of Leukemia and Lymphomas: New Therapeutic Targets.衰老和与年龄相关的表观遗传漂移在白血病和淋巴瘤发病机制中的作用：新的治疗靶点。
Cells. 2023 Sep 30;12(19):2392. doi: 10.3390/cells12192392.
4
Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt's lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib.克服EZH2抑制剂在伯基特淋巴瘤中的治疗局限性：MS1943与依鲁替尼联合效应的综合研究
Front Oncol. 2023 Sep 11;13:1252658. doi: 10.3389/fonc.2023.1252658. eCollection 2023.
5
Epigenetic alterations and advancement of lymphoma treatment.表观遗传学改变与淋巴瘤治疗进展。
Ann Hematol. 2024 May;103(5):1435-1454. doi: 10.1007/s00277-023-05395-z. Epub 2023 Aug 15.
6
SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities.SWI/SNF 复合物在血液系统恶性肿瘤中的作用：生物学意义和治疗机会。
Mol Cancer. 2023 Feb 21;22(1):39. doi: 10.1186/s12943-023-01736-8.
7
EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.EZH2-H3K27me3 介导的 KRT14 上调促进三阴性乳腺癌腹膜转移。
Nat Commun. 2022 Nov 29;13(1):7344. doi: 10.1038/s41467-022-35059-x.
8
Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases.组蛋白甲基转移酶中与癌症相关的错义突变的并行功能注释。
Sci Rep. 2022 Nov 2;12(1):18487. doi: 10.1038/s41598-022-23229-2.
9
Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis.zeste同源物2增强子（EZH2）是胃肠胰和呼吸道高级别神经内分泌肿瘤的标志物，并预示不良预后。
Cancers (Basel). 2022 Jun 8;14(12):2828. doi: 10.3390/cancers14122828.
10
Large-Scale Chromatin Rearrangements in Cancer.癌症中的大规模染色质重排
Cancers (Basel). 2022 May 12;14(10):2384. doi: 10.3390/cancers14102384.
本文引用的文献
1
Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.联合 EZH2 和 Bcl-2 抑制剂作为针对遗传定义的 DLBCL 亚型的精准治疗。
Blood Adv. 2020 Oct 27;4(20):5226-5231. doi: 10.1182/bloodadvances.2020002580.
2
Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.塔西美替尼治疗复发或难治性滤泡性淋巴瘤患者的疗效：一项开放标签、单臂、多中心、2 期临床试验。
Lancet Oncol. 2020 Nov;21(11):1433-1442. doi: 10.1016/S1470-2045(20)30441-1. Epub 2020 Oct 6.
3
Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma.CheckMate 140 研究的疗效和安全性结果，该研究是一项纳武利尤单抗治疗复发/难治性滤泡淋巴瘤的 2 期研究。
Blood. 2021 Feb 4;137(5):637-645. doi: 10.1182/blood.2019004753.
4
Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.突变 EZH2 通过重塑免疫反应诱导恶性前淋巴瘤生态位。
Cancer Cell. 2020 May 11;37(5):655-673.e11. doi: 10.1016/j.ccell.2020.04.004.
5
The conditional survival analysis of relapsed DLBCL after autologous transplant: a subgroup analysis of LY.12 and CORAL.自体移植后复发弥漫性大B细胞淋巴瘤的条件生存分析：LY.12和CORAL的亚组分析
Blood Adv. 2020 May 12;4(9):2011-2017. doi: 10.1182/bloodadvances.2020001646.
6
A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications.具有治疗意义的弥漫性大 B 细胞淋巴瘤遗传亚型的概率分类工具。
Cancer Cell. 2020 Apr 13;37(4):551-568.e14. doi: 10.1016/j.ccell.2020.03.015.
7
A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features.一项评估塔西美妥单抗（EPZ-6438）联合 R-CHOP 方案治疗伴有预后不良特征的新诊断弥漫性大 B 细胞淋巴瘤（DLBCL）患者的 LYSA Ib 期研究。
Clin Cancer Res. 2020 Jul 1;26(13):3145-3153. doi: 10.1158/1078-0432.CCR-19-3741. Epub 2020 Mar 2.
8
EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas.EZH2 抑制剂恢复 B 细胞淋巴瘤中表观遗传沉默的 CD58 表达。
Mol Immunol. 2020 Mar;119:35-45. doi: 10.1016/j.molimm.2020.01.006. Epub 2020 Jan 18.
9
Positron-emission tomography-based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma.基于正电子发射断层扫描的分期降低了滤泡性淋巴瘤患者早期疾病进展的预后影响。
Eur J Cancer. 2020 Feb;126:78-90. doi: 10.1016/j.ejca.2019.12.006. Epub 2020 Jan 8.
10
Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma.苯达莫司汀-利妥昔单抗治疗后早期进展与晚期滤泡性淋巴瘤转化风险高相关。
Blood. 2019 Aug 29;134(9):761-764. doi: 10.1182/blood.2019000258. Epub 2019 Jul 12.
Zotero 插件