Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer.

Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability – leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche.

IV期转移性乳腺癌患者的治疗仅限于姑息性方案，这是一项尚未满足的临床需求。在此，我们证明了对微小RNA - 10b（一种转移性细胞活力的主要调节因子）进行药理抑制，可在转移性乳腺癌小鼠模型中消除远处转移。这是通过使用微小RNA - 10b抑制性纳米药物MN - anti - miR10b实现的，该药物由磁性纳米颗粒与基于锁核酸（LNA）的微小RNA - 10b拮抗剂偶联而成。将MN - anti - miR10b静脉注射到患有乳腺癌肺、骨和脑转移的小鼠体内，导致纳米药物在转移性肿瘤细胞中选择性积聚。每周用MN - anti - miR - 10b和低剂量阿霉素对小鼠进行治疗，使65%的动物已有的远处转移完全消退，并显著降低了癌症死亡率。这些观察结果得到了转移部位增殖显著减少和凋亡增加的支持。在分子水平上，我们观察到HOXD10的表达显著增加，HOXD10是微小RNA - 10b的一个已知靶点。这些结果是迈向针对转移微环境的未知治疗领域的第一步。