Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Mari I Suominen,Katja M Fagerlund,Anniina Luostarinen,Esa Alhoniemi,Birgitta Sjöholm,Jukka P Rissanen,Jenni Mäki-Jouppila,Dominik Mumberg,Anna Huhtinen,Arne Scholz,Gerhard Siemeister,Sanna-Maria Käkönen

doi:10.3390/ijms22115570

Abstract

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.

Highlights

IntroductionIt is the most frequent malignancy to affect bone, with up to 80% of patients developing bone disease characterized by destructive bone lesions and an increased risk for skeletal fractures associated with increased morbidity and mortality [2,3,4]
Multiple myeloma (MM) is the second most common hematological malignancy [1]
We have previously demonstrated that radium-223 possesses a dual mode of action in prostate cancer bone metastasis mouse models: it inhibits tumor growth and suppresses tumorinduced pathological bone formation, which are both processes involved in the vicious cycle of osteoblastic bone metastases

Summary

Introduction

It is the most frequent malignancy to affect bone, with up to 80% of patients developing bone disease characterized by destructive bone lesions and an increased risk for skeletal fractures associated with increased morbidity and mortality [2,3,4]. Bortezomib is used either as a single agent or in combination treatment, for instance with immunomodulatory agents, steroids, or conventional chemotherapy drugs [6,7,8]. Besides their direct antiproliferative and cytotoxic effects in MM cells, bortezomib and other proteasome inhibitors have been shown to restore the impaired osteoblast activity typically observed in MM [9,10,11]

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