odanacatib and Neoplasm-Metastasis

Treatment and prevention of bone metastases is a major problem in patients with cancer. New treatment of bone metastases are needed to maintain the quality of life of our patients with metastastic bone disease. In addition, promising preliminary results suggest that bone-directed therapies may be able to prevent both skeletal and extraskeletal metastases. For the past decade intravenous bisphosphonates have been the mainstay of treatment of patients with bone metastases. New therapies such as the antibody to RANKL (denosumab) are undergoing phase III clinical testing. In addition, confirmatory studies suggesting that bisphosphonates can prevent metastatic disease are underway.. Understanding the biology of bone metastases has uncovered many new potential therapies for the treatment and prevention of bone metastases. Many of these potential new approaches are discussed in the enclosed article.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biphenyl Compounds; Bone Density Conservation Agents; Bone Neoplasms; Cathepsin K; Denosumab; Diphosphonates; Endothelin Receptor Antagonists; Humans; Neoplasm Metastasis; Quality of Life; RANK Ligand

Approximately 90% of patients with advanced breast cancer develop bone metastases; an event that results in severe decrease of quality of life and a drastic deterioration in prognosis. Therefore, to increase the survival of breast cancer patients, the development of new therapeutic strategies to impair metastatic process and skeletal complications is critical. Previous studies on the role of cathepsin K (CTSK) in metastatic spreading led to several strategies for inhibition of this molecule such as MIV-711 (Medivir), balicatib and odanacatib (ODN) which were on trial in the past. The present study intended to assess the anti-metastatic efficacy of ODN in breast cancer cells. Human breast cancer cell lines MDA-MB-231 were treated with different concentrations of ODN and performed invasion, adhesion and migration assays and, RT-PCR and western blot to evaluate the effect of ODN on the metastatic potential of breast cancer cells. ODN markedly decreased wound healing cell migration, invasion and adhesion at a dose dependent manner. ODN inhibits cell invasion by decreasing the matrix metalloproteinase (MMP-9) with the upregulation of TIMP-1 expression. ODN effectively inhibited the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal Kinase (JNK), and blocked the expression of β-integrins and FAK proteins. ODN also significantly inhibited PI3K downstream targets Rac1, Cdc42, paxillin and Src which are critical for cell adhesion, migration and cytoskeletal reorganization. ODN exerts anti-metastatic action through inhibition of signaling pathway for MMP-9, PI3K and MAPK. This indicates potential therapeutic effects of ODN in the treatment of metastatic breast cancer.

Topics: Benzamides; Biphenyl Compounds; Breast Neoplasms; Cathepsin K; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Organic Chemicals; Phosphatidylinositol 3-Kinases; Piperazines; Tissue Inhibitor of Metalloproteinase-1