title: Combination of the c-Met inhibitor tivantinib and zoledronic acid prevents tumor bone engraftment and inhibits progression of established bone metastases in a breast xenograft model.
abstract: Bone is the most common metastatic site for breast cancer. There is a significant need to understand the molecular mechanisms controlling the engraftment and growth of tumor cells in bone and to discover novel effective therapeutic strategies. The aim of this study was to assess the effects of tivantinib and Zoledronic Acid (ZA) in combination in a breast xenograft model of bone metastases. Cancer cells were intracardially implanted into immunodeficient mice and the effects of drugs alone or in combination on bone metastasis were evaluated by in vivo non-invasive optical and micro-CT imaging technologies. Drugs were administered either before (preventive regimen) or after (therapeutic regimen) bone metastases were detectable. In the preventive regimen, the combination of tivantinib plus ZA was much more effective than single agents in delaying bone metastatic tumor growth. When administered in the therapeutic schedule, the combination delayed metastatic progression and was effective in improving survival. These effects were not ascribed to a direct cytotoxic effect of the combined therapy on breast cancer cells in vitro. The results of this study provide the rationale for the design of new combinatorial strategies with tivantinib and ZA for the treatment of breast cancer bone metastases.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Previdi
authors.forename: Federica
authors.initials: F
authors.lastname: Scolari
authors.forename: Rosaria
authors.initials: R
authors.lastname: Chilà
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbadessa
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: C551661:ARQ 197; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011760:Pyrrolidinones; D011804:Quinolines; D000077211:Zoledronic Acid; D019859:Proto-Oncogene Proteins c-met