通过抑制 E-选择素靶向血液恶性肿瘤:急性髓细胞性白血病治疗的甜蜜点?

IF 6.9 2区 医学 Q1 HEMATOLOGY
Geoffrey L. Uy , Daniel J. DeAngelo , Jay N. Lozier , Dennis M. Fisher , Brian A. Jonas , John L. Magnani , Pamela S. Becker , Hillard M. Lazarus , Ingrid G. Winkler
{"title":"通过抑制 E-选择素靶向血液恶性肿瘤:急性髓细胞性白血病治疗的甜蜜点?","authors":"Geoffrey L. Uy ,&nbsp;Daniel J. DeAngelo ,&nbsp;Jay N. Lozier ,&nbsp;Dennis M. Fisher ,&nbsp;Brian A. Jonas ,&nbsp;John L. Magnani ,&nbsp;Pamela S. Becker ,&nbsp;Hillard M. Lazarus ,&nbsp;Ingrid G. Winkler","doi":"10.1016/j.blre.2024.101184","DOIUrl":null,"url":null,"abstract":"<div><p>E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewis<sup>x</sup>) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewis<sup>x</sup> that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.</p></div>","PeriodicalId":56139,"journal":{"name":"Blood Reviews","volume":null,"pages":null},"PeriodicalIF":6.9000,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0268960X24000171/pdfft?md5=6a37de75ade24871f4a8227183a16306&pid=1-s2.0-S0268960X24000171-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?\",\"authors\":\"Geoffrey L. Uy ,&nbsp;Daniel J. DeAngelo ,&nbsp;Jay N. Lozier ,&nbsp;Dennis M. Fisher ,&nbsp;Brian A. Jonas ,&nbsp;John L. Magnani ,&nbsp;Pamela S. Becker ,&nbsp;Hillard M. Lazarus ,&nbsp;Ingrid G. Winkler\",\"doi\":\"10.1016/j.blre.2024.101184\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewis<sup>x</sup>) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewis<sup>x</sup> that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.</p></div>\",\"PeriodicalId\":56139,\"journal\":{\"name\":\"Blood Reviews\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-02-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0268960X24000171/pdfft?md5=6a37de75ade24871f4a8227183a16306&pid=1-s2.0-S0268960X24000171-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood Reviews\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0268960X24000171\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0268960X24000171","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

E-选择素是一种细胞黏附性糖蛋白,在静脉内皮细胞上表达,介导白细胞定位到发炎的内皮,这是炎症细胞外渗到组织的第一步。骨髓内皮 E 选择素的持续表达还能通过 NF-κB 介导的信号支持骨髓造血。相应地,E-选择素与急性髓性白血病(AML)细胞上的 E-选择素配体(sialyl Lewisx)相互作用会导致体内化疗的抗药性。Uproleselan(GMI-1271)是sialyl Lewisx的碳水化合物类似物,可阻断E-选择素的结合。一项 MEC 化疗联合 uproleselan 治疗复发/难治性急性髓细胞白血病的 2 期试验显示,中位总生存期为 8.8 个月,严重口腔黏膜炎的发生率较低(2%)。临床试验旨在确认其在急性髓细胞白血病中的活性,并减轻强化化疗后由中性粒细胞介导的不良反应(粘膜炎和腹泻)。在这篇综述中,我们总结了E-选择素的生物学特性以及将uproleselan与其他疗法联合治疗血液恶性肿瘤的理由。我们还介绍了 uproleselan 的药理作用和正在进行的临床试验。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Blood Reviews
Blood Reviews 医学-血液学
CiteScore
13.80
自引率
1.40%
发文量
78
期刊介绍: Blood Reviews, a highly regarded international journal, serves as a vital information hub, offering comprehensive evaluations of clinical practices and research insights from esteemed experts. Specially commissioned, peer-reviewed articles authored by leading researchers and practitioners ensure extensive global coverage across all sub-specialties of hematology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信