Project Details
Projekt
Regulation, integration and impact of NFkB-signaling within the oncogenic signaling network in multiple myeloma
Subject Area
Hematology, Oncology
Term
from 2009 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 100308792
In the first funding period we found that the NFκB system is far from being maximally activated in myeloma cells and its activity could consequently be boosted exogenously by stimulation of TNF receptors or treatment with SMAC mimetics. Noteworthy, such exogenous stimulation of the NFκB system showed no major protective effect against various drugs targeting oncogenic pathways and even enhanced sensitivity for the endogenous apoptosis inducer CD95L by upregulation of its receptor CD95. We also found that individual as well as dual inhibition of the classical and alternative NFκB pathways using the IKK2-specifc inhibitors TPCA1, the NEDD8-activating enzyme inhibitor MLN4924 or IKK1 and IKK2 knockdown elicited no or a rather mild cytotoxic effect in short term assays (12-48 h). The myeloma-supporting activity of stromal cells, however, was strongly reduced by inhibitors of NFκB signaling. Thus, the NFκB system appears less important for myeloma cell survival as initially anticipated but could be of crucial relevance for myeloma cells beyond sole apoptosis protection and might further be required to maintain a myeloma compatible microenvironment.Based on these results, we now want to address the following four issues: First, in view of our own findings on the complex regulatory role of the two TNF receptors TNFR1 and TNFR2 on extrinsic apoptosis of myeloma cells and clinical evidence arguing for relevance of the TNF-TNF receptor system in MM, we want to evaluate in more detail the therapeutic potential of TNF and TNF receptor targeting reagents in MM. For this, we will analyze in cooperation with project Z1 treatment regimes in syngeneic MM models that allow selective exogenous stimulation of TNFR1 or TNFR2 with and without concomitant blockade of endogenous TNF. Most NFκB-related mutations affect molecules that act upstream of NIK and the IKKs. Because these molecules also act outside the NFκB system, we will secondly address the possibility that such NFκB-independent functions contribute to the MM phenotype. Specifically, we will investigate whether in myeloma cells crosstalk between NIK and/or IKK1 with Wnt, Notch and STAT3 signaling exists. Thirdly, many of the NFκB-related mutations found in MM affect components or inducers of the TRAF2-cIAP1/2 complex, which not only inhibits alternative NFκB signaling but also stimulates classical NFκB signaling and moreover inhibits the caspase-8 activating ripoptosome. Therefore, we will evaluate in vitro and in vivo whether MM cells are particularly prone to the therapeutic effects of the ripoptosome activating SMAC mimetic BV6. Finally, to identify in an unbiased fashion NFκB-dependent and -independent IKK/NIK-regulated targets, SILAC/mass spectrometry screens will be performed in co-operation with project Z4N using various inhibitors targeting distinct stages of NFκB signaling.
DFG Programme
Clinical Research Units
