Bone Abstracts

Breast to bone metastasis is a common incurable event during breast cancer progression. Identifying the molecular mechanisms at play is vital for the development of new therapies. Matrix metalloproteinases, such as MMP-2, are overexpressed in the bone metastatic microenvironment. Genetic ablation of MMP-2 demonstrated its importance of in driving osteolytic bone metastatic breast cancer and support the rationale for the development of a highly specific MMP-2 inhibitor for the eradication of active bone metastatic breast cancer.

Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful due to dose limiting systemic side effects, we utilized a novel chemical approach to synthesize bone seeking MMP inhibitors (BMMPIs) on a bisphosphonic backbone, with specificity for MMP-2 (IC₅₀=140 nM). In vitro, we tested the effect of BMMPIs on the viability of the major cellular components of the cancer-bone microenvironment (breast cancer cells, osteoblasts and osteoclasts). In vivo, mice received intratibially luciferase expressing breast cancer cells and were then treated with vehicle, zoledronate or BMMPIs (1mg/kg). Tumor growth was determined via luminescence quantitation. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. MMP activity in vivo and ex vivo was determined via specific activatable MMP probes. We observed that BMMPIs significantly impacted the viability of breast cancer cells and osteoclasts in vitro compared to control. In vivo BMMPIs significantly reduced the growth of bone metastatic breast cancer and MMP activity compared to control and zoledronate. Ex vivo analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions (up to 80% by μCT; P<0.05).

In conclusion, MMP-2 specific BMMPIs prevent bone metastatic breast cancer growth by impacting cancer cell viability and cancer induced osteolysis. We predict that BMMPIs could be translated to the clinic for the treatment and eradication of bone metastatic breast cancer.