Maternal Embryonic Leucine Zipper Kinase Inhibitor OTSSP167 Inhibits Osteoclast Activity and Restores Osteoblast Activity in a Murine Model of Multiple Myeloma Bone Disease

Multiple myeloma bone disease (MMBD) is characterized by an increased osteoclast activity and a decreased osteoblast differentiation in the multiple myeloma (MM) microenvironment, resulting in the development of lytic bone lesions. A large majority of MM patients suffer from MMBD, which not only causes morbidity but also negatively impacts patient survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lytic lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that maternal embryonic leucine zipper kinase (MELK) drives a high-risk gene network in MM and that MELK inhibition with OTSSP167 reduces tumor development in the 5TGM.1 model. In the current study, we assessed the effect of OTSSP167 treatment on bone cell activity and the development of MMBD.

OTSSP167 inhibited osteoclast activity in vitro by decreasing monocytic progenitor cell viability as well as via a direct anti-resorptive effect on mature osteoclasts in both human (derived from PBMCs) and murine (RAW264.7) cell cultures. In addition, OTSSP167 stimulated matrix deposition and mineralization by human BMSC-TERT osteoblasts in vitro, which coincided with an increased expression of osterix . This combined anti-resorptive and osteoblast-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in MM-bearing 5TGM.1 mice, as assessed by micro-computed tomography. OTSSP167 reduced the number of cortical perforations in MM-bearing mice, without affecting cortical thickness. The loss of trabecular bone volume that occurs in MM-bearing mice compared to healthy controls, was completely prevented, due to an increase in the number of trabeculae and a decrease in trabecular separation. Immunohistomorphometric analyses on the femurs of these mice showed that the increase in osteoclast surface observed in MM-bearing mice was completely prevented with OTSSP167 treatment. In addition, OTSSP167 treatment resulted in a recovery of osteoblast and osteoid surface levels.

In conclusion, we show that OTSSP167 has a direct anti-MMBD effect in addition to its anti-MM activity, which warrants further clinical development of MELK inhibition in MM.

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