AbstractAlong 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.
|Date of Award||24 Apr 2018|
|Supervisor||Karin Vanderkerken (Promotor), Henri Schots (Promotor), Eline Menu (Promotor), Els Van Valckenborgh (Promotor), Bart Neyns (Jury), Ivan Van Riet (Jury), Damya Laoui (Jury), Steven Pals (Jury) & Fritz Offner (Jury)|
- Multiple Myeloma