Abstract
Abstract Cabozantinib is an inhibitor of tyrosine kinases including MET, VEGFR2, and RET, and has shown clinical activity in patients with castration-resistant prostate cancer and other solid tumors with bone metastases. Multiple myeloma (MM) is the second most common hematologic malignancy, and represents ∼2% of all cancer deaths. MM is a monoclonal B-cell (plasma cell) neoplasia with clinical hallmarks of multiple osteolytic lesions causing bone pain, pathologic fractures, and hypercalcemia. Circulating levels of HGF and VEGF are upregulated in MM patients, and regulation of plasma cell-osteoblast communication by the HGF-MET signaling pathway has been implicated in the development of lytic bone disease in these patients. Thus, our aim was to determine the activity of cabozantinib on bone lesions and tumor burden in the syngeneic 5TGM1 mouse MM model. Four experimental groups were included: negative control group receiving vehicle, positive control group receiving bortezomib (0.5 mg/kg ip twice a week), low dose cabozantinib group (10 mg/kg, PO QD) and high dose cabozantinib group (30 mg/kg, PO QD). Female C57BL/KaLwRij mice were allocated to treatment groups (n=15 per group) with equivalent average body weights. On day 0, animals were inoculated with 5TGM1 mouse myeloma cells by IV administration. Dosing began on day 1 and continued daily until euthanasia at day 35. Body weights were determined twice a week and blood samples were collected on days -1, 15, 22, and 34 for analysis of paraprotein (IgG2b) and TRACP 5b. The development of osteolytic lesions was detected by radiography at the end of the study. Some animals (4/15) were euthanized before the end of the experiment due to paraplegia in control and bortezomib groups, but none in cabozantinib groups. Animals euthanized within four days of the end of the experiment were included in the analysis. Bortezomib reduced serum IgG2b levels and decreased the frequency of soft tissue lesions, but did not show bone protective properties. Cabozantinib exhibited bone protective effects: mean and total area of osteolytic lesions were reduced at the 30 mg/kg dose, and serum TRACP 5b values and osteoclast counts at the tumor-bone interface were reduced at both the 10 and 30 mg/kg doses. Relative bone area did not differ from control according to histomorphometry. The rise in serum IgG2b started earlier than vehicle control in both cabo-treated groups, but a significant difference was not observed in relative IgG2b at sacrifice. Cabozantinib dose dependently increased the necrotic tumor area in bone, indicating the possibility that the rise in IgG2b may have been due to lysis of plasma cells. Both cabozantinib doses decreased the frequency of soft tissue lesions. In summary, cabozantinib showed both bone-protective and anti-tumor effects in this murine model of MM. Based on these promising results, further investigation of cabozantinib in multiple myeloma is warranted. Citation Format: Mari I. Suominen, Douglas O. Clary, Rami Käkönen, Katja M. Fagerlund, Esa Alhoniemi, Jukka P. Rissanen, Jussi M. Halleen, Dana T. Aftab. Effects of Cabozantinib in the 5TGM1 murine multiple myeloma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 734. doi:10.1158/1538-7445.AM2014-734
Published Version
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