Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer.
Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer.
复制标题
DOI：
10.1038/srep45060
复制
发表时间：
2017-03-21
影响因子：
4.6
通讯作者：
Medarova Z
中科院分区：
文献类型：
--
作者：
Yoo B;Kavishwar A;Wang P;Ross A;Pantazopoulos P;Dudley M;Moore A;Medarova Z
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。
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.