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

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.

Fig. 1.

Gene organization and structure of E-selectin and related selectins [–30]. A: Genes for P-selectin (SELP), E-selectin (SELE), and L-selectin (SELL) comprise a cluster on chromosome 1 at 1q24. B: The E-selectin gene contains 14 exons that encode the E-selectin protein. C: E-selectin is highly glycosylated, comprising lectin, epidermal growth factor-like (EGF), short consensus-repeat (SCR), and transmembrane/cytoplasmic domains (left). The lectin domain, also known as the carbohydrate recognition domain, binds to oligosaccharide carbohydrates sialyl Le^a and sialyl Le^x. Selectin proteins vary in number of SCR domains (right).

Fig. 2.

Circulating neutrophils roll on endothelium expressing E-selectin under the influence of inflammatory cytokines (TNFα and IL-1) [24]. Sialyl Lewis^x on the neutrophil surface mediates binding to endothelial cells that express E-selectin. These interactions lead to neutrophil arrest and subsequent extravasation from the bloodstream.

Fig. 3.

Chemical structure of glycomimetic, E-selectin antagonist, uproleselan (sodium salt), C₆₀H₁₀₈N₃NaO₂₇, molecular weight 1326.5 Da.

Fig. 4.

Model of uproleselan docked into the E-selectin carbohydrate-recognition domain (CRD) of E-selectin, based on the RCSB Protein Data Bank crystal structure of E-selectin [80,81].

Fig. 5.

Synergy of uproleselan with chemotherapy for AML in mice. Four human AML cell lines (panels A-D) and one mouse AML cell line (panel E) were tested for response to chemotherapy +/− uproleselan in various inbred mouse lines. A: Human AML blasts in NOD-SCID mice, Rx with DNR/AraC +/− uproleselan 10 mg/kg or 40 mg/kg [82]. B: Human AML cell line U937 in NOD-SCID mice, Rx with DNR/AraC +/− uproleselan 40 mg/kg [82]. C: KG1-luc human AML cell line in NOD-SCID mice, Rx with AZA +/− uproleselan 40 mg/kg [83]. D: Human AML-PDX cells in NOD-SCID mice, Rx with VEN/AZA +/− uproleselan 40 mg/kg [84]. E. Mouse monomyelocytic leukemia cells induced by retroviral MLL-AF9-ires-GFP cells in C57BL/6 mice, Rx DOX/AraC +/− uproleselan 40 mg/kg [18]. All P values reflect survival difference significance between chemotherapy with uproleselan versus chemotherapy alone.