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Targeting bone as a therapy for myeloma.

ABSTRACT: Myeloma bone disease (BD) not only impairs quality of life, but is also associated with impaired survival. Studies of the biology underlying BD support the notion that the increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and a necessity for tumour growth and clonal expansion. Survival and expansion of the myeloma clone is dependent on its interactions with bone elements, thus targeting these interactions should have antimyeloma activities. Indeed both experimental and clinical findings indicate that bone-targeted therapies not only improve BD, but also create an inhospitable environment for myeloma cell growth and survival, favouring improved clinical outcome. This review summarizes recent progress in our understandings of the biology of myeloma BD, highlighting the role of osteoclasts and osteoblasts in this process and how they can be targeted therapeutically. Unravelling the mechanisms underlying myeloma-bone interactions will facilitate the development of novel therapeutic agents to treat BD, which as a consequence are likely to improve the clinical outcome of myeloma patients.

SUBMITTER: Wu P

PROVIDER: S-EPMC3234321 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Targeting bone as a therapy for myeloma.

Wu Ping P Morgan Gareth J GJ

Cancer microenvironment : official journal of the International Cancer Microenvironment Society 20110811 3

Myeloma bone disease (BD) not only impairs quality of life, but is also associated with impaired survival. Studies of the biology underlying BD support the notion that the increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and a necessity for tumour growth and clonal expansion. Survival and expansion of the myeloma clone is dependent on its interactions with bone elements, thus targeting these interactions should have antimyeloma activities. Indeed both experim ...[more]

PMID: 21833747

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Project description:An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

Targeting bone as a therapy for myeloma.

Publications

Targeting bone as a therapy for myeloma.

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