Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

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

Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

Blood Rev. 2024 May:65:101184. doi: 10.1016/j.blre.2024.101184. Epub 2024 Feb 28.

Authors

Geoffrey L Uy¹, Daniel J DeAngelo², Jay N Lozier³, Dennis M Fisher⁴, Brian A Jonas⁵, John L Magnani⁶, Pamela S Becker⁷, Hillard M Lazarus⁸, Ingrid G Winkler⁹

Affiliations

¹ Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ GlycoMimetics, Inc., Rockville, MD, USA. Electronic address: [email protected].
⁴ P Less Than, San Francisco, CA, USA.
⁵ Department of Internal Medicine, Division of Malignant Hematology/Cellular Therapy and Transplantation, University of California Davis, Davis, CA, USA.
⁶ Glycotech, Inc., Rockville, MD, USA.
⁷ Leukemia Division, Department of Hematology and Hematopoietic Cell Transplantation, Department of Hematologic Malignancies Translational Science, City of Hope National Medical Center, Duarte, CA, USA.
⁸ Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁹ Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Woolloongabba, QLD, Australia.

Abstract

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^x) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewis^x 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.

Keywords: Acute myeloid leukemia (AML); E-selectin; Hematologic malignancies; Selectin; Uproleselan.

Publication types

Review

MeSH terms

Bone Marrow / pathology
E-Selectin / antagonists & inhibitors
E-Selectin / metabolism
Endothelial Cells / metabolism
Hematologic Neoplasms* / drug therapy
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / pathology

Substances

E-Selectin

Grants and funding

R50 CA275927/CA/NCI NIH HHS/United States