Abstract
The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma. Patients with elevated levels of HGF have a poor prognosis, therefore, targeting these entities in such patients may be of substantial benefit. We hypothesized that ARQ-197 (Tivantinib), a small molecule c-Met inhibitor, would reduce myeloma cell growth and prevent myeloma-associated bone disease in a murine model. In vitro we assessed the effects of ARQ-197 on myeloma cell proliferation, cytotoxicity and c-Met protein expression in human myeloma cell lines. In vivo we injected NOD/SCID-γ mice with PBS (non-tumour bearing) or JJN3 cells and treated them with either ARQ-197 or vehicle. In vitro exposure of JJN3, U266 or NCI-H929 cells to ARQ-197 resulted in a significant inhibition of cell proliferation and an induction of cell death by necrosis, probably caused by significantly reduced levels of phosphorylated c-Met. In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group. However, no significant differences on bone parameters were observed in non-tumour mice treated with ARQ-197 compared to vehicle, implying that in tumour-bearing mice the effects of ARQ-197 on bone cells was indirect. In summary, these res ults suggest that ARQ-197 could be a promising therapeutic in myeloma patients, leading to both a reduction in tumour burden and an inhibition of myeloma-induced bone disease.
Highlights
Multiple myeloma (MM) is a cancer of differentiated B-cells, characterised by the accumulation of malignant plasma cells (MPCs) in the bone marrow
In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group
We demonstrate the efficacy of ARQ-197 on the JJN3, U266 and NCI-H929 human myeloma cell lines in vitro and its effects in vivo on tumour burden and bone disease in the JJN3-NSG murine model of MM
Summary
Multiple myeloma (MM) is a cancer of differentiated B-cells, characterised by the accumulation of malignant plasma cells (MPCs) in the bone marrow. Common clinical manifestations include bone marrow failure leading to anaemia, impaired immunity and thrombocytopaenia, renal failure and a destructive bone disease caused by the disruption of normal bone remodelling, stimulation of osteoclastic bone resorption and inhibition of osteoblastic bone formation. Myeloma bone disease is characterised by hypercalcaemia, focal lytic lesions leading to pathological fractures, severe pain and functional deficit. MM remains a predominantly incurable disease with patients having a median survival time of only 7 to 8 years [13]. This necessitates the need to identify new targets for drug development to reduce the tumour load and prevent further tumour-induced bone disease
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