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Role of c-Met and VEGFR2 in breast cancer bone metastases

Breast cancer commonly metastasizes to bone, causing pain and fracture. During tumor development, cells within the expanding tumor are deprived of oxygen which results in induction of mediators of angiogenesis including VEGF, MET and VEGFR2. Both osteoblasts and osteoclasts express MET and VEGFRs. Cabozantinib (cabo, XL184) is a balanced inhibitor of MET and VEGFR2. Cabo treatment in preclinical models results in tumor regression and blockade of tumor invasiveness and metastasis. To elucidate the mechanisms of cabo activity we are studying a human breast cancer bone xenograft model. Female nude mice are inoculated with MDA-MB-231 cells via the left cardiac ventricle and treated with cabozantinib after detection of osteolytic lesions on x-ray (approx. 13 days). Mice treated with cabo exhibited less weight loss as vehicle-treated mice and a reduction in osteolytic lesion area. Cabo treatment also reduced the intensity of photon emission from tumors as measured by optical imaging using a Cathepsin K-linked fluorescent probe. Finally, mice treated with cabo had significantly improved survival. Studies to further characterize the molecular mechanisms underlying these effects are ongoing.