针对临床常用标准治疗方案验证骨转移技术平台

Bone metastases are a significant clinical problem in many major cancers, especially in breast and prostate cancer where 70-90% of advanced patients develop bone metastases. Myeloma bone disease is associated with similar clinical problems than bone metastases. Current cancer therapies can only partially decrease tumor growth in bone, resulting in only 5% of bone metastatic patients being alive 5 years after the diagnosis. Bone metastases decrease the quality of life of patients due to cancer-induced bone loss that leads to increased risk of fractures and bone pain. Bone metastases are therefore a high unmet medical need with a high demand for effective therapies. Lack of appropriate preclinical bone metastasis models that would exhibit the same clinical features and responses to therapies that are observed in bone metastatic patients has made it difficult to advance therapy development at early stages. In this study, we validated our previously established Bone Metastasis Technology Platform (BMTP©) against standard-of-care (SOC) therapies in triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) bone metastasis models, and in a multiple myeloma (MM) bone disease model. In this study, we used the following cell lines and mouse strains: 4T1 mouse TNBC cells in BALB/c mice, RM-1 mouse CRPC cells in C57BL/6 mice, and human RPMI 8226 MM cells in immunodeficient NPG mice. Intratibial inoculation into the bone marrow was used to model tumor growth in bone. Tumor growth was monitored by bioluminescence imaging, cancer-induced bone changes by X-ray imaging, and bone pain by Von Frey filaments (mechanical allodynia). SOC treatments included doxorubicin (4 mg/kg, ip, BIW) in the TNBC model, docetaxel (10 mg/kg, ip, BIW) in the CRPC model, bortezomib (0.5 mg/kg, ip, BIW) in the MM model, and zoledronic acid (0.1 mg/kg, QW) in all models as an inhibitor of cancer-induced bone loss. In the TNBC model, doxorubicin decreased tumor growth and both doxorubicin and zoledronic acid decreased bone loss. Neither therapy was effective in reducing bone pain. In the CRPC model, docetaxel decreased tumor growth and zoledronic acid decreased bone loss, but no effects were observed on bone pain. In the MM model, bortezomib decreased tumor growth and zoledronic acid decreased bone loss. These results demonstrate that BMTP shows the same clinical features and responses to therapies that are observed in patients with TNBC, CRPC and MM. We conclude that BMTP is a clinically relevant translational tool for evaluating efficacy of cancer therapies on bone metastasizing cancers.