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
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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.

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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.
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