Clinical Development of First-in-Class Therapy for Metastatic Breast Cancer

我们已经开发出一种新的治疗方法，依赖于特定的转移瘤根除 通过药物抑制miRNA-10b作用于肿瘤细胞。MIR-10b是一款主调节器 转移性肿瘤细胞的生存能力，并已被彻底验证为一个有前途的治疗靶点 在18种转移性癌症类型的100多项临床研究中。这种方法依赖于一种治疗性的 在转移细胞中特异性抑制microRNA-10b的试剂。治疗性(称为MN-抗- MiR10b)由超小的葡聚糖包覆的氧化铁纳米颗粒(MN)组成，连接到 靶向miRNA-10b的反交配子。在我们的临床前研究中，我们发现这种疗法 静脉注射后，通过淋巴结、肺、骨和脑中转移的肿瘤细胞 注射。我们证明了miR-10b抑制疗法可以诱导持久的消退。 没有系统性证据的乳腺癌小鼠模型中的淋巴转移和远处转移 毒性。具体地说，每周只有四到六次MN-抗miR10b联合Low治疗 剂量化疗导致可检测到的转移完全消退。在消除了 转移，治疗停止了。在自然生活中没有观察到复发。 动物。在这个应用中，我们建议执行关键的翻译实验，包括IND- 启用和IND支持的成像研究，评估MN-anti-miR10b的摄取 放射学证实的乳腺癌患者的转移性病变，作为进入 I期临床试验。

We have developed a new therapeutic approach that relies on specific eradication of metastatic tumor cells through pharmacological inhibition of miRNA-10b. miR-10b is a master regulator of the viability of metastatic tumor cells and has been thoroughly validated as a promising therapeutic target in over 100 clinical studies across 18 metastatic cancer types. The approach relies on a therapeutic agent that specifically inhibits microRNA-10b in metastatic cells. The therapeutic (termed MN-anti- miR10b) consists of ultrasmall dextran-coated iron oxide nanoparticles (MN), conjugated to antagomirs targeting miRNA-10b. In our preclinical studies, we found that the therapeutic is taken up avidly by metastatic tumor cells in the lymph nodes, lungs, bone, and brain, following intravenous injection. We demonstrated that the miR-10b inhibitory therapeutic could elicit durable regression of lymph node and distant metastases in mouse models of breast cancer with no evidence of systemic toxicity. Specifically, just four to six weekly treatments with MN-anti-miR10b in combination with low dose chemotherapy led to complete regression of detectable metastases. Following elimination of metastases, therapy was discontinued. No recurrence was observed for the natural life of the animals. In this application, we propose to perform key translational experiments including IND- enabling and IND-supported imaging studies that would assess the uptake of MN-anti-miR10b by radiologically confirmed metastatic lesions in breast cancer patients, as a final step before entry into phase I clinical trials.