A New MicroRNA-1291 Replacement Therapy for Pancreatic Cancer Disease

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因。显然需要更有效的疗法来治疗致命的胰腺癌疾病。microRNA（miRNA或miR）是一大组短的非编码RNA，其控制人类细胞中的转录后基因表达，并且越来越多的证据表明在人类癌中存在失调的肿瘤抑制和致癌miRNAs。在癌组织中下调的肿瘤抑制miRNA可以通过称为“miRNA替代疗法”的新方法重新引入癌细胞中以阻断肿瘤生长。我们已经鉴定了一种肿瘤抑制miRNA，miR-1291，与正常胰腺导管组织相比，其在人胰腺导管腺癌（PDAC）中的表达水平降低。将miR-1291模拟物重新引入PDAC细胞中诱导癌细胞周期停滞和异种移植胰腺肿瘤生长的抑制。鉴于miR-1291在PDAC中表现出功能丧失的肿瘤抑制作用，该STTR I期项目被提议严格评估用于治疗胰腺癌的新的“miR-1291替代疗法”技术。具体而言，目的1是证明miR-1291替代疗法在临床相关动物模型中控制胰腺肿瘤生长的有效性，目的2是建立miR-1291复合在临床相关药物递送系统中的药代动力学和安全性特征。I期的成功完成将确定一种治疗性miR-1291制剂，该制剂将成为临床前开发的主题，以准备II期的IND申请。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. There is a clear need for more effective therapies to treat deadly pancreatic cancer disease. MicroRNAs (miRNA or miR) are a large group of short, noncoding RNAs that control posttranscriptional gene expression in human cells, and there is increasing evidence for the existence of tumor suppressive and oncogenic miRNAs deregulated in human carcinomas. A tumor suppressor miRNA down-regulated in cancerous tissues may be reintroduced into cancer cells via a novel approach, known as "miRNA replacement therapy", to block tumor growth. We have identified a tumor suppressor miRNA, miR-1291, that is expressed at reduced levels in human pancreatic ductal adenocarcinoma (PDAC) compared to normal pancreatic ductal tissue. The reintroduction of miR-1291 mimics into PDAC cells induces cancer cell cycle arrest and the suppression of xenograft pancreatic tumor growth. Given the tumor suppressive role for miR-1291 that exhibits a loss-of-function in PDAC, this STTR Phase I project is proposed to critically assess a new "miR-1291 replacement therapy" technology to treat pancreatic cancer. Specifically, Aim 1 is to demonstrate the effectiveness of miR-1291 replacement therapy in control of pancreatic tumor growth in clinically relevant animal models, and Aim 2 is to establish the pharmacokinetic and safety profiles of miR-1291 complexed in clinically relevant drug delivery system. Successful completion of Phase I will identify a therapeutic miR-1291 formulation that will be the subject of pre-clinical development in preparation of an IND submission in Phase II.