Blood Cancer Journal | 2019
Inhibition of E-Selectin (GMI-1271) or E-selectin together with CXCR4 (GMI-1359) re-sensitizes multiple myeloma to therapy
Abstract
Dear Editor, Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow (BM) characterized by continuous metastasis. MM remains incurable, despite the improved overall survival of MM patients due to clinically introduced novel treatments such as proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (IMiDs; lenalidomide). The complex cross-talk between MM cells and the tumor microenvironment (TME) facilitates tumor progression and therapy resistance. Adhesion molecules such as selectins and C-X-C chemokine receptor type 4 (CXCR4, CD184) play pivotal roles in advancement of MM, suggesting that these molecules could be targeted to reduce metastasis and overcome drug resistance. Elevated CXCR4 expression enables MM cells’ dissemination from the primary tumor site to the peripheral blood (PB) and further to a new BM site attracted by chemokines such as stromal-derived growth factor-1 (SDF-1). Homing of MM is initiated through interaction between ligands present on MM cells such as cutaneous lymphocyte-associated antigen (CLA; role of which is not well described in MM) and adhesion molecules Eand P-selectin expressed on vascular endothelium, which induce rolling, adhesion, and extravasation. Most of cancer therapies consist of targeting the MM cells directly; however, recently disrupting MM interactions with the TME through inhibiting adhesion of cancer cells to the TME or hindering the homing of already circulating tumor cells thus preventing metastasis have been suggested as therapeutic strategies. In this study, we tested the effect of blocking E-selectin alone using GMI-1271 and blocking both E-selectin and CXCR4 using GMI-1359 on TME disruption in order to sensitize MM cells to chemotherapy. First, analysis of CXCR4, CLA, and E-selectin mRNA expression in CD138+ plasma cells isolated from newly diagnosed MM patients using the Gene Expression Omnibus database showed (mean ± s.e.m.) 18,223.19 ± 452.04, 3472.67 ± 118.01, and 42.16 ± 2.01, respectively (Fig. 1a). Interestingly, CLA expression in CD138+ plasma cells was the highest among patients with MM (3472.67 ± 118.01) compared to monoclonal gammopathy of undetermined significance (2459.96 ± 270.13) and healthy donors (1910.85 ± 107.72) (Fig. 1b). This data suggests that CXCR4 mRNA is highly expressed in newly diagnosed MM patients and that CLAmRNA expression significantly increases with MM advancement. We have previously demonstrated that MM progression and dissemination was hypoxia dependent, and hypoxic MM cells had improved cell trafficking, increased tumor initiation, and induced drug resistance contributing to minimal residual disease and relapse. Natoni et al. demonstrated that the CLA was increased in hypoxic MM cells implying disease progression, and CLA expression was further augmented in MM cells from relapsed/refractory patients compared to newly diagnosed patients. These results suggest that CLA undergoes dynamic changes with MM development and could potentially be a biomarker of disease progression and drug resistance. However, we found that CLA expression was negligible and restricted to a small subpopulation of MM cells (1.3% MM.1S, 0.9% H929 and 6.3% U266) (Fig. 1c)