Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions are painful and currently, despite medical advances, are incurable. Therefore, identifying the underpinning molecular mechanisms in the bone microenvironment is vital for the development of new therapies. Gene expression analysis and validation in human and murine specimens of bone metastases revealed matrix metalloproteinases, such as MMP-2, are highly expressed in the bone metastatic microenvironment. These data 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 in the nanomolar range (IC50=140 nM). Based on our previous data about BMMPI’s ability to significantly reduce breast cancer growth in the bone microenvironment, we decided to investigate the role of BMMPI such as ML115 in preventing dissemination of cancer cells into the skeleton. Balb-c female mice (n = 10/group), pretreated for 7 days with vehicle, standard of care bisphosphonate (Zoledronate= 1 mg/kg) and BMMPIs (ML115= 1 mg/kg), were randomized and intra-cardiac injected with luciferase expressing 4T1 (2x105) breast cancer cell line. Tumor growth was assessed via luminescence quantitation overtime.
Our preliminary total body bioluminescent data suggest that pretreatment with ML115 can significantly reduce the amount of breast cancer cells homing into the bone, compared to vehicle and standard bisphosphonate. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. Ex vivo analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions. We are currently measuring MMP activity in vivo and ex vivo via specific activatable MMP probes, in order to confirm BMMPI mechanism of action.
We predict that BMMPIs could be used as preventive treatment to impair breast cancer to bone metastasis in clinic.
H Lee Moffitt Cancer Center.
Susan G Komen Breast Cancer Foundation and American Airlines.
All authors have declared no conflicts of interest.