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Br J Haematol. 2017 Oct;179(1):36-49. doi: 10.1111/bjh.14807. Epub 2017 Jul 2.

CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma.

Author information

1
Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2
Clinical Trials Unit, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3
Department of Internal Medicine II, Translational Oncology/CCC Mainfranken, University Hospital Würzburg, Würzburg, Germany.
4
Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Abstract

Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR.

KEYWORDS:

adhesion molecules; drug resistance; multiple myeloma; stem cell mobilizing/homing; stroma cells

PMID:
28670693
DOI:
10.1111/bjh.14807
[Indexed for MEDLINE]

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