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 , Daniel J. DeAngelo , Jay N. Lozier , Dennis M. Fisher , Brian A. Jonas , John L. Magnani , Pamela S. Becker , Hillard M. Lazarus , 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 , Daniel J. DeAngelo , Jay N. Lozier , Dennis M. Fisher , Brian A. Jonas , John L. Magnani , Pamela S. Becker , Hillard M. Lazarus , 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}
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.
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.