Bone marrow-induced survival: identifying novel targets in multiple myeloma.

Along with the continuous introduction of new therapeutic agents, overall survival of multiple myeloma (MM) patients has significantly improved. However, the majority will eventually relapse and become refractory to treatment. Both cellular and non-cellular components of the bone marrow microenvironment play a crucial role in the development of resistance, including a complex (BM) interplay of cytokines, chemokines, growth factors, exosomes, proteolytic enzymes and adhesion molecules. A better insight in these processes may lead to new therapeutic strategies. We explored different BM microenvironment targeting strategies in the immunocompetent 5TMM model. In a first project, we explored the role of tumor-associated macrophages (TAMs) on myeloma cell survival and drug resistance. We found that the macrophage-induced pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells. In a second project, we found that T. brucei induced intrinsic apoptosis of 5T33MM cells in vivo, and that this effect was associated with reduced endogenous unfolded protein response (UPR) activation. The effect of novel therapeutic agents was also investigated in the 5TMM model. Treatment with the integrin inhibitor G038887 had no direct effect on tumor load but was able to prolong survival. We also examined the effect of the Bruton tyrosine kinase inhibitor ibrutinib on MM cell survival and the BM microenvironment but were not able to detect a significant impact on tumor load or bone destruction.