Abstract 2867: Glycomimetic antagonist of E-selectin, GMI-1271, enhances therapeutic activity of the hypomethylating agent 5-azacitidine in the KG1 model of AML
Authors: Smith Theodore A. , Fogler William E. , Lee Ji-Won , Magnani John L. 
Published: August 2018

Binding of AML blasts to E-selectin activates cellular survival pathways leading to chemoresistance. GMI-1271 is a novel E-selectin antagonist that when used in combination with chemotherapy results in improved survival in mouse syngeneic and xenogeneic AML tumor models. GMI-1271 in combination with two chemotherapy regimens is in early clinical trials for the treatment of AML. Azacitidine (5-AC) is a DNA-methyltransferase inhibiting cytosine nucleoside analog that at low doses induces DNA hypomethylation and transcriptional activation, while at higher doses is directly cytotoxic to neoplastic cells including AML blasts. 5-AC is approved in Europe for the treatment of limited populations with AML. We evaluated GMI-1271 in combination with 5-AC in the KG1 AML tumor model to assess the potential for therapeutic benefit of the combination.

NSG mice (10/group) received i.v. injections of KG1 cells, and were treated with saline, GMI-1271 alone, 5-AC alone, or the combination of GMI-1271 and 5-AC. The median survival time (MST) of mice treated with 5-AC was 88 days and statistically different (P&lt;0.002) to groups treated with saline (MST=69.5 days) or GMI-1271 alone (MST=69 days). All mice treated with saline or GMI-1271 alone succumbed to progressive tumor growth. At study conclusion (Day 104 post tumor injection) 20% of mice treated with 5-AC remained alive. Importantly, the therapeutic activity of 5-AC was significantly enhanced when combined with GMI-1271 (MST&gt;104 days, P=0.0140 compared to 5-AC alone) with 70% of mice surviving to study conclusion. These results indicate that E-selectin/AML blast interaction in the KG1 model protects from the anti-tumor activity of 5-AC and that GMI-1271 attenuates this protection.

To investigate the nature of the observed in vivo activity of GMI-1271 and 5-AC, KG1 cells were cultured for 96 h in a noncytotoxic concentration (100 nM) of 5-AC and the reactivity of the cells to HECA-452 (an antibody that recognizes an E-selectin carbohydrate ligand) and binding to E-selectin were determined by flow cytometry. Treatment with 5-AC resulted in a 28% increase in reactivity of cells to HECA-452 and a 32% increase in binding to E-selectin. Further in vitro assays of static adhesion revealed an increase in the adhesion of 5-AC-treated KG1 cells to E-selectin. Notably, the enhanced adhesion of KG-1 cells to E-selectin was reversed using GMI-1271. Collectively, these results demonstrate that 5-AC can lead to increased expression of E-selectin ligands on AML cells and that the therapeutic potential of 5-AC could be improved by combination with GMI-1271.

Citation Format: Theodore A. Smith, William E. Fogler, Ji-Won Lee, John L. Magnani. Glycomimetic antagonist of E-selectin, GMI-1271, enhances therapeutic activity of the hypomethylating agent 5-azacitidine in the KG1 model of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2867.