Combination with zoledronic acid (ZA) and sunitinib (SU) to reduce severity of osteolytic lesions in bone metatstases.

Abstract

1089 Background: Skeletal metastases are observed frequently in patients with breast cancer (BC). High osteoclast activity with bone resorption is a feature of most bone metastases. Bisphosphonates are established as the main treatment. The treatment delays the rate at which skeletal-related events occur and with regards to study results provide a DFS benefit to patients with early BC. This opens the possibility of new preventive treatment regimens that could interfere with the tumor cell-osteoclast interaction. SU is an oral multitarget TKI that demonstrated anti-angiogenesis activity. In this study the preventive potential of a SU and ZA combination is tested in a mouse xenograft model of breast cancer bone metastases. Methods: DsRed2-labelled bone-metastatic MDA-MB231 cells were injected into the left ventricle of nude mice. One group of mice (n=10 each) was treated with 40mg/kg SU (orally/daily), another group were treated with ZA at 20ug/kg/week, starting one day before injection of tumor cells. A third group was given the combination of SU and ZA and the fourth group was injected with vehicle control only. Tumor development was monitored by measuring fluorescent signals in vivo and x-ray measurements. Osteolytic lesions were monitored by optical imaging using near infrared bone mineral binding dyes Osteosense 680 and Bonetag injected i.p. Results: Nonradiographic detection of metastatic lesions correspond to metastatic lesions as confirmed by x-ray measurements (mm2). Numbers of lesions as analyzed by x-ray and immunohistochemistry are significantly less after 6 weeks of treatment with the combination of SU and ZA compared to monotherapy. The preventive protocol with ZA and SU does not increase survival. Conclusions: In this model of bone metastases, combination treatment with ZA and SU resulted in a significant reduction in the extent of osteolytic skeletal lesions in bone as compared to zoledronic acid treatment alone. The near infrared bone mineral binding dyes may be a future alternative to x-ray measurements in assessing osteoblastic and osteolytic lesions in bone metastases and gives insights into disease biology. No significant financial relationships to disclose.