Clinically Representative Bone Metastasis Models: Key Drivers in Oncology Drug Development

Background: /Objectives: Triple-negative breast cancer (TNBC), castration-resistant pros-tate cancer (CRPC), and multiple myeloma (MM) are common cancers associated with high incidence of bone metastases, leading to high mortality, severe pain and reduced quality of life. Preclinical drug development in these cancers typically focuses solely on primary tumors, overlooking the critical bone metastatic tumor microenvironment that plays a key role in the unique aspects of osteo-immuno-oncology, highlighting the need for clinically predictive bone metastasis models. The aim of this study was to establish preclinical models that represent clinical features of bone metastases in patients and serve as predictive tools to drive drug development. Methods: TNBC, CRPC and MM cells were inoculated into the bone marrow of mice. Tumor growth was monitored by biolumines-cence imaging (BLI), cancer-induced bone loss by scoring X-ray images, and bone pain by von Frey filaments. Results: All mice developed bone metastases, with high tumor burden observed at days 21, 28, and 56 in the TNBC, CRPC, and MM models, respectively. Tu-mor-induced osteolytic, osteoblastic or mixed bone changes closely resembled those seen in patients. Bone pain, a key indicator of quality of life, correlated with tumor burden and bone loss. Conclusions: The established preclinical models accurately represent clinical features, including tumor-induced bone changes and pain, that are observed in bone met-astatic TNBC, CRPC and MM patients. Given their clinical presentation, these models should be integrated into drug development to reliably assess novel therapies in these in-dications, with a proper focus on bone metastases.