Abstract 786: Effects of combination treatment with cabozantinib and bortezomib in the 5TGM1 murine multiple myeloma model
Authors: Suominen Mari I. , Fagerlund Katja M. , Alhoniemi Esa , Rissanen Jukka P. , Halleen Jussi M. , Aftab Dana T. 
Published: August 2015

Abstract
Cabozantinib (cabo) is an inhibitor of tyrosine kinases including MET, VEGFR2, RET, and the TAM family kinases TYRO3, AXL, and MER, and has shown clinical activity in patients with castration-resistant prostate cancer and other solid tumors with bone metastases. Multiple myeloma (MM) is a monoclonal B-cell (plasma cell) neoplasia representing ∼2% of all cancer deaths. The clinical hallmark is presence 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. We have previously shown that cabo is active in the syngeneic 5TGM1 mouse MM model. This study aimed to determine whether combination with bortezomib would yield additional benefit.
Four experimental groups were included: 1) Control group receiving vehicle, 2) Bortezomib (0.5 mg/kg ip twice a week), 3) Cabo (10 mg/kg, PO QD) and 4) Combination (bortezomib + cabo, same doses).
Female C57BL/KaLwRij mice were allocated to treatment groups (n = 15 per group) with equivalent average body weights. At day 0, animals were inoculated with 5TGM1 cells by IV administration. Dosing began at day 1 and continued daily until euthanasia. Body weights were determined twice a week and blood samples were collected at days -1, 16, 23, 35 and at sacrifice for analysis of paraprotein (IgG2b), PINP and TRACP 5b. Development of osteolytic lesions was detected by radiography at day 35 and at sacrifice. Mice were sacrificed individually when they became paraplegic, lost over 20% of body weight, or had severe breathing problems. The maximum length of the study was 70 days.
By study day 35, the osteolytic lesions were not affected by bortezomib, were reduced by cabo alone, and further reduced by the combination treatment. Bortezomib had inhibited the rise in serum IgG2b levels, but cabo and the combination treatment had not. Despite the effects on serum IgG2b, bortezomib did not significantly increase survival, whereas cabo and the combination treatment did. Increased survival with the combination was significant when compared to bortezomib monotherapy, but not when compared to cabo monotherapy. Earlier we have shown that cabo dose-dependently increases the necrotic tumor area in bone, and proposed that the rise in IgG2b was due to lysis of plasma cells and not tumor growth. Consistent with this hypothesis, the IgG2b levels of cabo treated mice were lower at sacrifice than at day 35 in this study.
In summary, cabo increased survival and exhibited bone-protective and anti-tumor effects in this murine model of MM. Combination with bortezomib showed additive effects on survival. Based on these results, further investigation of cabozantinib in multiple myeloma is warranted.
Citation Format: Mari I. Suominen, Katja M. Fagerlund, Esa Alhoniemi, Jukka P. Rissanen, Jussi M. Halleen, Dana T. Aftab. Effects of combination treatment with cabozantinib and bortezomib in the 5TGM1 murine multiple myeloma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 786. doi:10.1158/1538-7445.AM2015-786