A new target for myeloma therapy

From bloodjournal.hematologylibrary.org by guest on February 14, 2012. For personal use only.

2012 119: 1325-1326 doi:10.1182/blood-2011-12-394486

A new target for myeloma therapy
Rauf Haznedar

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From bloodjournal.hematologylibrary.org by guest on February 14, 2012. For personal use only.

inside blood
9 FEBRUARY 2012 I VOLUME 119, NUMBER 6 ● ● ● LYMPHOID NEOPLASIAComment on Azab et al, page 1468

A new target for myeloma therapy ---------------------------------------------------------------------------------------------------------------Rauf Haznedar
˙ GAZI UNIVERSITY MEDICAL SCHOOL

In this issue of Blood, Azab and colleagues demonstrate that PSGL-1 expressed on myeloma cells is involved with regulating tumor cell extravasation, homing, diseaseprogression, and drug resistance.1

Down-regulation of PSGL-1 in MM cells or inhibition of selectin with antibody reversed drug resistance induced by BM stromal cells in mice treated with bortezomib.

ver the past two decades, treatment for multiple myeloma has improved with the use of high-dose melphalan therapy with peripheral blood stem cell support and novel drugs including thalidomide,bortezomib, and lenalidomide. In younger patients, survival now extends beyond 10 years. In elderly myeloma patients, obtaining complete remission has become the goal of therapy with the use of novel drug combinations. Myeloma cell– microenvironment interactions are crucially important in understanding disease biology and pathogenesis.2 After the discovery of IL-6, we have learned that insulin-likegrowth factor-1, vascular endothelial growth factor, and tumor necrosis factor also promote myeloma cell proliferation. Microenvironment bone marrow stroma not only contribute to my-

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eloma cell growth and survival, but also produce proangiogenic factors and contribute to drug resistance and bone disease.2,3 Proteasome inhibitors and the immunomodulatory drugs (ImiDs) thalidomide andlenalidomide affect the microenvironment in addition to directly killing myeloma cells. IMiDs enhance immune response to myeloma cells, enhance natural killer cell function, stimulate T-cell proliferation and CD8 T-cell activation, and increase IL-2 and IFN levels.4 Bortezomib supresses the expression of CD49d at mRNA level, down-regulates VLA-4, and may help overcome cell adhesion–mediated drugresistance.5 Bortezomib inhibits ostoclastogenesis and stimulates bone formation. It can be used in combination to treat myeloma bone disease.

Despite these advances, multiple myeloma is still an incurable disease. Myeloma patients, having worse genetic features, have poorer response to therapy and survival is short. Apart from the reported high-risk features, cell adhesion–mediated drug resistanceplays a role in treatment failure. Although the proteasome inhibitor bortezomib helps overcome drug resistance to some extent, we clearly need new approaches. Targeted therapy with monoclonal antibodies has given rise to great hope in hematologic malignancies. We need to develop more effective drugs and more efficient antibodies. Currently targeted therapy with cyclindependent kinases4/6 and VEGF...