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

我们已经开发了一种新的治疗方法，依赖于特异性根除转移性 肿瘤细胞通过药理学抑制miRNA-10 b。miR-10 b是一个主要的调节因子， 转移性肿瘤细胞的活力，并已被彻底验证为有前途的治疗靶点 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方法， 在转移性细胞中特异性抑制microRNA-10 b的试剂。治疗（称为MN-抗- miR 10 b）由超小的葡聚糖包被的氧化铁纳米颗粒（MN）组成，其缀合至 靶向miRNA-10 b的药物。在我们的临床前研究中，我们发现， 在静脉内给药后，淋巴结、肺、骨和脑中的转移性肿瘤细胞贪婪地 注射我们证明了miR-10 b抑制治疗可以引起持久的消退， 淋巴结和远处转移的小鼠乳腺癌模型，没有全身性 毒性具体地说，仅用MN-抗miR 10 b与低剂量的miR 10 b联合治疗4至6周， 剂量化疗导致可检测到的转移完全消退。在消除 转移，停止治疗。在自然寿命内未观察到复发。 动物在本申请中，我们建议进行关键的翻译实验，包括IND- 启用和IND支持的成像研究，将评估MN-抗-miR 10 b的摄取， 在乳腺癌患者中，放射学证实的转移性病变，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.