Abstract 5005: Inhibition of E-selectin or E-selectin together with CXCR4 resensitizes multiple myeloma to treatment
Authors: Muz Barbara , Bazai Henna Y. , Sekula Anita , Fogler William E. , Smith Ted , Magnani John L. , Azab Abdel Kareem 
Published: July 2017

INTRODUCTION: Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow. Selectins and CXCR4 play a pivotal role in homing, adhesion, and proliferation of MM. Herein, we tested the role of E-selectin in the pathophysiology of MM by using a specific E-selectin antagonist (GMI-1271) and a dual E-selectin/CXCR4 antagonist (GMI-1359) on the proliferation and cell trafficking of MM in vitro and in vivo.

PROCEDURES: Endothelial cells (HUVECs), stromal cells (HS5), MM patient-derived stromal cells (MSP1), and MM cell lines (MM1s, H929, U266 and RPMI8226) were tested for expression of E-selectin, CLA (E-selectin ligand) and CXCR4 by flow cytometry. The effect of GMI-1271 and GMI-1359 was studied on MM cell adhesion to stroma; chemotaxis to stromal media or SDF1; and MM cell survival by MTT assay, where MM cells were treated with lenalidomide or carfilzomib; in the presence, or absence of GMI-1271 or -1359. In a xenograft mouse model, the sensitivity of MM was tested in mice treated with vehicle, lenalidomide, GMI-1271, or a combination of GMI-1271 and lenalidomide (n=10 mice/group); and tumor growth was monitored weekly using bioluminescence imaging.

SUMMARY: Expression of E-selectin was high in HUVECs, MSP1 and HS5; CLA was high only in RPMI8226; and CXCR4 was high in all MM cells. MM1s cell adhesion to stroma was decreased by GMI-1271 and even more profoundly decreased by GMI-1359 in a dose-dependent manner. Chemotaxis of MM1s cells towards conditioned media or SDF1 was modestly affected by GMI-1271, but greatly reduced by GMI-1359. MM cell proliferation was significantly inhibited by GMI-1359, only when MM cells were co-cultured with stroma, but not alone. Stroma-induced drug resistance of MM cells to carfilzomib and lenalidomide was reduced in the presence of the GMI compounds, while the effect of GMI-1359 was stronger than GMI-1271. In vivo, GMI-1271 and lenalidomide as single agents delayed tumor growth compared to vehicle by 40% and 35%, respectively; however, a combination treatment delayed tumor growth more profoundly than vehicle by 64% (p=0.04).

CONCLUSIONS: GMI-1271 and GMI-1359 disrupt the interaction between MM cells and bone marrow microenvironment as determined by reduction of adhesion, chemotaxis and microenvironment-induced drug resistance in vitro. However, the dual inhibition of E-selectin and CXCR4 produced more profound effects compared to E-selectin alone. Moreover, GMI-1271 sensitized MM cells to lenalidomide by alleviating chemoresistance and delayed tumor growth in vivo.

Citation Format: Barbara Muz, Henna Y. Bazai, Anita Sekula, William E. Fogler, Ted Smith, John L. Magnani, Abdel Kareem Azab. Inhibition of E-selectin or E-selectin together with CXCR4 resensitizes multiple myeloma to treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5005. doi:10.1158/1538-7445.AM2017-5005