Effects Of Cabozantinib On Breast Cancer Bone Metastases, Overall Survival, And Bone Mass In A Mouse Model

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 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