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.
背景/目的：晚期乳腺癌患者可能发生骨转移，导致剧烈疼痛、病理性骨折甚至死亡。现有治疗方案疗效有限，亟需开发靶向治疗方法。骨转移性乳腺癌细胞分泌的甲状旁腺激素相关蛋白（PTHrP）可促进肿瘤生长并加速骨质破坏。既往研发的PTH/PTHrP拮抗剂因半衰期短且骨靶向性不足而在临床试验中受挫。本研究评估了两种新型骨靶向PTH拮抗剂——通过胶原蛋白结合域（CBD）融合增强骨定位能力的PTH(7-33)-CBD与[W2]PTH(1-33)-CBD。方法：采用小鼠胫骨内及髂骨内乳腺癌模型，评估药物在减轻肿瘤负荷与骨破坏方面的疗效。结果：生物发光成像、X射线及显微CT分析显示，两种药物均较对照组显著降低肿瘤负荷并抑制骨溶解，其中[W2]PTH(1-33)-CBD还能改善骨小梁微结构。该疗效在胫骨与髂骨肿瘤模型中均得到验证。结论：本研究证实CBD融合型PTH/PTHrP拮抗剂可作为乳腺癌骨转移的潜在治疗策略。
Bone Targeted Parathyroid Hormone Antagonists for Prevention of Breast Cancer Bone Metastases
肿瘤(癌症)患者之家