Bone Targeted Parathyroid Hormone Antagonists for Prevention of Breast Cancer Bone Metastases

BACKGROUND/OBJECTIVES: Advanced breast cancer patients may develop bone metastases, leading to severe pain, fractures, and mortality. Current treatments have limited efficacy, necessitating targeted therapy approaches. Bone metastatic breast cancer cells secrete PTHrP that promotes tumor growth and bone degradation. Previous PTH/PTHrP antagonists failed clinically due to short half-life and insufficient bone targeting. The present study evaluated the following two novel bone-targeted PTH antagonists fused to a collagen-binding domain (CBD) for enhanced bone localization: PTH(7-33)-CBD and [W2]PTH(1-33)-CBD. METHODS: Intra-tibial and intra-iliac breast tumor models in mice were used to evaluate drug efficacy in reducing tumor burden and bone destruction. RESULTS: Bioluminescent imaging, X-ray, and micro-CT analysis revealed that both drugs significantly reduced tumor burden and osteolysis compared to control, with [W2]PTH(1-33)-CBD additionally improving trabecular bone structure. Drug efficacy was confirmed in both intra-tibial and intra-iliac breast tumor models. CONCLUSIONS: These findings identify CBD-fused PTH/PTHrP antagonists as a promising therapeutic strategy for breast cancer bone metastases.