Page 123 - Haematologica August 2018

Plasma Cell DIsorders
Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity in multiple myeloma bone disease
Joséphine Muller,1,a Arnold Bolomsky,2,a Sophie Dubois,1 Elodie Duray,1 Kathrin Stangelberger,2 Erwan Plougonven,3 Margaux Lejeune,1 Angélique Léonard,3 Caroline Marty,4 Ute Hempel,5 Frédéric Baron,1,6 Yves Beguin,1,6 Martine Cohen-Solal,4 Heinz Ludwig,2 Roy Heusschen1,b and Jo Caers1,6,b
Ferrata Storti Foundation
1Laboratory of Hematology, GIGA-I3, University of Liège, Belgium; 2Wilhelminen Cancer Research Institute, Department of Medicine I, Wilhelminenspital, Vienna, Austria; 3PEPs (Products, Environments, Processes), Chemical Engineering, Liège, Belgium; 4INSERM- UMR-1132, Université Paris Diderot, France; 5Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany
Haematologica 2018 Volume 103(8):1359-1368
and 6Department of Hematology, CHU de Liège, Belgium
aJoséphine Muller and Arnold Bolomsky are co-first authors. bRoy Heusschen and Jo Caers are co-senior authors.
ABSTRACT
Multiple myeloma bone disease is characterized by an uncoupling of bone remodeling in the multiple myeloma microenviron- ment, 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 develop- ment 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 stim- ulated 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 corroborat- ed 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.
Introduction
The development of lytic bone lesions due to multiple myeloma bone disease (MMBD) is a hallmark of multiple myeloma (MM).1 MMBD occurs in more than 80% of MM patients2 and is caused by an uncoupling of bone remodeling. MMBD not only results in morbidity but also directly stimulates MM tumor growth through multiple mechanisms, resulting in a vicious cycle of bone destruction and MM growth.3,4 Although novel therapies continue to increase the life expectancy for MM patients, lytic bone lesions in these patients rarely heal.4 Bisphosphonates are the current standard of care for MMBD but can be respon-
Correspondence:
jo.caers@chu.ulg.ac.be
Received: November 26, 2017. Accepted: May 3, 2018. Pre-published: May 10, 2018.
doi:10.3324/haematol.2017.185397
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1359
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