Therapy for Metastatic breast cancer based on micro RNA silencing

转移性乳腺癌患者的治疗选择非常有限， 姑息治疗代表未满足的临床需求。先前的研究表明，microRNA在 在包括来自乳腺癌的转移的形成中起重要作用。考虑到缺乏 乳腺癌转移患者的选择，在这项提案中，我们专注于靶向miR-10 b 被证明是导致转移性扩散的原因虽然先前的研究表明miR-10 b驱动了侵袭， 和癌细胞从原发肿瘤的迁移，我们最近的发现表明，在转移性细胞中， 也负责细胞活力和增殖，转移性细胞的存活关键取决于 miR-10 b的高水平表达。这一发现构成了我们治疗策略的基石， 特异性根除转移性肿瘤细胞。这将通过使用具有成像能力的模块化纳米药物来完成， 其分布于肺、肝、骨或脑转移瘤。这些纳米药物由磁性纳米颗粒组成 其携带抑制microRNA-10 b的锁核酸（LNA）寡核苷酸。靶向部分缀合 纳米颗粒促进了它们在远处转移部位的积累。之前我们已经证明了 所提出的方法的可行性。将纳米药物递送到已经形成的淋巴结 转移通过抑制肿瘤细胞增殖导致转移进展停滞， 细胞凋亡，这是一种以前没有描述过的现象。当用纳米药物治疗 结合低剂量的常规化疗（阿霉素）， 消除淋巴结或肺转移，即使在停止治疗后也无复发。不像 常规化疗，该治疗方案与动物发病率/死亡率无关。在 在当前的应用中，我们提出将miR 10 b抑制性纳米药物与低剂量的 化疗（必要时），以靶向远处器官的乳腺癌转移。无创 成像将用于评价纳米药物的递送。如果成功的话，这种方法可能会成为一种生活- 为晚期转移性疾病患者提供延长（并可能挽救生命）的替代方案， 挽救治疗是目前唯一的选择。

Treatment options for patients with metastatic breast cancer are severely limited and ultimately rely on palliative care representing an unmet clinical need. Previous studies have demonstrated that microRNAs play a significant role in the formation of metastasis including those from breast cancer. Considering the paucity of options for patients with metastasis from breast cancer, in this proposal we focused on targeting miR-10b proven to be responsible for metastatic spread. While previous studies showed that miR-10b drives invasion and migration of cancer cells from primary tumors, our recent discovery demonstrated that in metastatic cells it is also responsible for cell viability and proliferation and that survival of metastatic cells crucially depends on the high level of miR-10b expression. This discovery formed a cornerstone of our therapeutic strategy aimed at specific eradication of metastatic tumor cells. This will be done using imaging-capable modular nanodrugs, which distribute to lung, liver, bone, or brain metastases. These nanodrugs consist of magnetic nanoparticles that carry locked-nucleic acid (LNA) oligonucleotides inhibiting microRNA-10b. Targeting moieties conjugated to the nanoparticles facilitate their accumulation at distant metastatic sites. Previously we have demonstrated the feasibility of the proposed approach. Delivery of the nanodrug to lymph nodes with already formed metastases resulted in arrest of metastatic progression by inhibiting tumor cell proliferation and causing apoptosis, which is a phenomenon that has not been described before. When treatment with the nanodrug was combined with a low-dose of conventional chemotherapy (doxorubicin), there was regression and permanent elimination of lymph node or lung metastases without relapse even after treatment was discontinued. Unlike conventional chemotherapies, this therapeutic protocol was not associated with animal morbidity/mortality. In the current application we propose to use the miR10b-inhibitory nanodrug in combination with low-dose chemotherapy (where necessary) for targeting breast cancer metastases in distant organs. Noninvasive imaging will be used to evaluate the delivery of the nanodrug. If successful, this approach could be a life- extending (and possibly, life saving) alternative for patients with advanced metastatic disease for whom salvage therapy is the only current option.