Abstract 733: Effects of cabozantinib on breast cancer bone metastases, overall survival, and bone mass in a mouse model
Authors: Mohammad Khalid S. , Harhash Ahmed , John Sutha K. , Peng Xianghong , Niewolna Maria , Murthy Sreemala , Laird A. Douglas , Aftab Dana T. , Guise Theresa A. 
Published: May 2015

Abstract
Rapid tumor growth results in tumor hypoxia and the induction of key mediators of angiogenesis including VEGF and MET. Cells in the bone microenvironment, including osteoblasts and osteoclasts, express MET and VEGFRs and respond to HGF and VEGF. Cabozantinib (cabo) is an inhibitor of tyrosine kinases including MET, VEGFR2, and RET. Cabo treatment in preclinical models results in tumor regression and blockade of tumor invasiveness and metastasis, and has shown clinical activity in patients with castration-resistant prostate cancer and breast cancer tumors with bone metastases. To elucidate the mechanisms underlying some of these clinical observations, the effects of cabo were studied in a human breast cancer bone xenograft and in a non-tumor bearing model. Female nude mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated with cabo (10 or 60 mg/kg/day). Treatment was initiated 13 days after tumor inoculation when osteolytic lesions were detectable on x-ray, and continued for 11 days. In a non-tumor model, female nude mice (∼5 weeks old) were treated with similar doses for 28 days. Tumor-bearing mice treated with cabo 60 mg/kg showed a reduction in osteolytic lesion area as measured by x-ray (p&lt;0.05). Cabo treatment at both doses reduced the intensity of photon emission from tumors as measured by optical imaging using a Cathepsin K-linked fluorescent probe (p&lt;0.01). Histomorphometric analysis showed a reduction in tumor burden in mice treated with cabo 60 mg/kg (p&lt;0.05). This was accompanied by reduction in osteoclast numbers at the tumor bone interface with cabo 60 mg/kg (p&lt;0.01) and 10 mg/kg (P&lt;0.05). Mice treated with cabo 60 mg/kg did not exhibit as much weight loss as vehicle-treated mice (P&lt;0.05). Mice treated with cabo at both doses showed significantly improved survival compared with vehicle treated mice (p&lt;0.01). In non-tumor bearing mice, bone mineral density (BMD) increased at the tibia with cabo 60 mg/kg (p&lt;0.001). MicroCT data analysis showed that treatment of mice with cabo 60 mg/kg resulted in an increase in trabecular bone volume (TBV) at the femur (p&lt;0.001), tibia (p&lt;0.001) and lumbar spine (p&lt;0.05). This was accompanied by an increase in trabecular thickness (p&lt;0.001) and connectivity density (femur p&lt;0.001, tibia p&lt;0.01), a reduction in trabecular spacing (p&lt;0.001 tibia & femur), and an increase in structure model index (p&lt;0.001). No difference was detected in cortical bone parameters with either dose. In conclusion, cabo reduced osteolytic lesions, reduced tumor burden, reduced osteoclast number and improved survival in mice with established breast cancer bone metastases, and increased trabecular bone volume in non-tumor bearing mice. Studies to further characterize the molecular mechanisms underlying these effects are ongoing.
Note: This abstract was not presented at the meeting.
Citation Format: Khalid S. Mohammad, Ahmed Harhash, Sutha K. John, Xianghong Peng, Maria Niewolna, Sreemala Murthy, A. Douglas Laird, Dana T. Aftab, Theresa A. Guise. Effects of cabozantinib on breast cancer bone metastases, overall survival, and bone mass in a mouse 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 733. doi:10.1158/1538-7445.AM2014-733