Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity in multiple myeloma bone disease

Abstract

Multiple myeloma bone disease is characterized by an uncoupling of bone remodeling in the multiple myeloma microenvironment, resulting in the development of lytic bone lesions. Most myeloma patients suffer from these bone lesions, which not only cause morbidity but also negatively impact survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that MELK plays a central role in proliferation-associated high-risk multiple myeloma and its inhibition with OTSSP167 resulted in decreased tumor load. MELK inhibition in bone cells has not yet been explored, although some reports suggest that factors downstream of MELK stimulate osteoclast activity and inhibit osteoblast activity, which makes MELK inhibition a promising therapeutic approach. Therefore, we assessed the effect of OTSSP167 on bone cell activity and the development of myeloma-induced bone disease. OTSSP167 inhibited osteoclast activity in vitro by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature osteoclasts. In addition, OTSSP167 stimulated matrix deposition and mineralization by osteoblasts in vitro. This combined anti-resorptive and osteoblast-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in myeloma-bearing mice. Immunohistomorphometric analyses corroborated our in vitro findings. In conclusion, we show that OTSSP167 has a direct effect on myeloma-induced bone disease in addition to its anti-multiple myeloma effect, which warrants further clinical development of MELK inhibition in multiple myeloma.

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

“…Several studies have reported that MELK acts as an oncogene in many kinds of tumours from multiple systems. [33][34][35][36][37][38] In this study, we cycle, DNA repair and replication, which was similar to previous reports. 6,26,33,[39][40][41][42][43] Next ous studies.…”

“…Several studies have reported that MELK acts as an oncogene in many kinds of tumours from multiple systems . In this study, we confirmed the oncogenic role of MELK in bladder tumorigenesis and elucidated for the first time the regulatory mechanism of MELK inhibition in BCa cells by bioinformatics analysis as well as in vitro/ in vivo investigation.…”

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

“…Osteoclast differentiation and resorptive activity were studied as previously described 13 , 14 . Briefly, RAW264.7 cells were initially seeded in αMEM medium supplemented with recombinant murine sRANKL (Peprotech, London, UK) at day 1.…”

The anti‐mitotic agents PTC‐028 and PTC596 display potent activity in pre‐clinical models of multiple myeloma but challenge the role of BMI‐1 as an essential tumour gene

“…In vivo experiments were performed using the 5TGM.1 murine model of myeloma as previously described. 19 These experiments were approved by the ethical committee for animal experiments of the University of Li ege (ULg license #16-1897). Treatment was initiated 1 day after the injection of myeloma cells (9-week-old female mice were injected i.v.…”