Anti-myeloma strategies by re-establishing bone regeneration and hematopoietic niches

• Applicant: Professorin Dr. Regina Ebert
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 179902948

Multiple myeloma (MM) inhibits bone and blood regeneration by various mechanisms, including stem cell niche conditioning with altered stem cell lineage commitment, uncoupling of angiogenesis and osteogenesis, and promotion of osteolytic vicious cycles. We have identified several new target mechanisms for modulating the stem cell niche and mesodermal commitment induced by contact between myeloma and MSC, such as (I) impaired lineage commitment for osteogenesis and altered angiogenesis and adipogenesis (ROR1, BMPER); (II) induction of new premetastatic niches and competitive hijacking of preformed stem cell niches (CXCR4/SDF-1, EBF2, JAM2/3); and (III) progression of myeloma bone disease (KISS1R, proapoptotic signaling via GPR). Based on these results we hypothesize that these targets can be addressed for sensitive molecular imaging, restoration of blood and bone regeneration and specific myeloma treatment. Our specific aims for the second funding period are to target contact-induced/repressed candidates and signaling systems in order to (I) investigate the biological relevance of inhibitors for lineage commitment and of disintegrators of angiogenesis, (II) to elucidate molecular mechanisms of niche modulation and T-cell response in myeloma bone disease depending on local oxygen tension, and (III) to define the relevance of the KISS1R system for bone regeneration and its potential for imaging and site-specific targeting. The general strategy is to evaluate lead candidates as diagnostic and therapeutic targets using stepwise characterization in 2D cell culture, 3D co-cultures in the BioVaSc device in bone marrow, preclinical models (e.g. MOPC315.BM) and validate these findings in human material from MM patients. These studies should paradigmatically integrate the bone and bone marrow niche into anti-tumor strategies. Reestablishing niches and pathways for bone and blood regeneration may confer anti-myeloma efficacy.

• DFG Programme: Research Units
• Subproject of: FOR 1586: SKELMET - Mesenchymal and Osteogenic Signalling Pathways in Malignant Bone Diseases
• Co-Investigators: Professor Dr. Franz Jakob; Professor Dr. Norbert Schütze