R21 MPI microRNA directed therapy for treating early stage pancreatic cancer

项目摘要 胰腺导管腺癌（PDAC）目前是美国第三大致死性癌症。是 目前是美国第三大癌症相关死亡病例，到本世纪末， 预计胰腺癌将超过结肠直肠癌，使其成为美国第二大致命癌症， 仅次于肺癌。胰腺癌的预后不良部分是由于晚期诊断。 被诊断为胰腺癌的患者通常在最初的一年或更短的时间内死于这种疾病。 诊断.胰腺癌的新发病率和死亡率几乎相同，强调了这一事实 几乎所有被诊断为胰腺癌的患者最终都会死于这种疾病。因此，我们认为， 发展策略以改善胰腺癌的早期诊断和治疗是至关重要的。在 在小鼠中，胰腺癌前体病变-胰腺上皮内肿瘤或PanIN之前是 腺泡导管化生（ADM）的过程。microRNA（miRNA）是一类小的非编码RNA， 表观遗传调节这些过程。我们以前的研究表明，miRNAs的肿瘤抑制作用 在MIR 217宿主基因内编码的，即miR-216 a、-216 b和-217。这些miRNAs是胰腺富集的 在胰腺腺泡中占主导地位，但在癌前阶段表达减少（ADM和 PanIN）和PDAC。基于这些发现，我们假设miR-216 a恢复到细胞中， 胰腺通过腺泡细胞靶向纳米颗粒（NPs）可以转移早期癌症病变， 腺泡状态，减少PanIN和PDAC的形成。为了验证我们的假设，我们将优化 通过筛选树枝状聚合物-脂质文库将miRNA有效递送至腺泡细胞的纳米颗粒制剂 本发明涉及用于高递送效力、低毒性和低免疫原性的纳米颗粒（DLNP）制剂。的能力 将在体外3-D测定中研究NP配制的miR-216 a和NP本身抑制体外ADM的作用。 DLNP将被工程化以靶向糖蛋白2（GP 2），糖蛋白2是由细胞特异性表达的细胞表面标志物。 正常腺泡细胞和那些经历了配制成抗GP 2 DLNP的ADM. miR-216 a寡核苷酸的腺泡细胞 将评价最大耐受剂量、毒性、生物分布和疗效。 胰腺癌的大多数治疗方法都集中在晚期治疗上，然而， 可能改善PDAC患者临床结果的早期预防性治疗尚未被 研究了我们研究了纳米治疗药物在胰腺癌发生前早期靶向胰腺腺泡细胞的潜力。 PDAC的开始。如果在临床上实施，这种疗法将使胰腺癌高风险的个体 通过生物标志物鉴定的癌症，在早期阶段接受治疗方案的施用， 从而获得更好的临床结果。

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is currently the third most lethal cancer in the United States. It is currently the third leading of cancer-related deaths in the United States and by the end of this decade, pancreatic cancer is predicted to pass colorectal cancer, making it the second most lethal cancer in the USA, second only to lung cancer. The poor prognosis of pancreatic cancer is in part due to the late-stage diagnosis. Patients diagnosed with pancreatic cancer typically succumb to the disease within a year or less of initial diagnosis. New incidence and death rates from pancreatic cancer are almost identical, emphasizing the fact that nearly all patients diagnosed with pancreatic cancer will eventually die of the disease. Therefore, developing strategies to improve the early diagnosis and treatment of pancreatic cancer is critical. In mice, pancreatic cancer precursor lesions – pancreatic intraepithelial neoplasms or PanINs are preceded by the process of acinar ductal metaplasia (ADM). microRNA (miRNA) is a class of small noncoding RNAs that epigenetically regulate these processes. Our previous studies suggest the tumor suppression role of miRNAs encoded within the MIR217 host gene, i.e. miR-216a, -216b, and -217. These miRNAs are pancreas enriched with predominate expression in pancreatic acini but are reduced during the pre-malignant stages (ADM and PanIN) and in PDAC. Based on these discoveries, we hypothesize that restoration of miR-216a to the pancreas through an acinar cell-targeting nanoparticles (NPs) can shift the early-stage cancer lesion to the acinar state, reducing PanIN and PDAC formation. To test our hypothesis, we will optimize the nanoparticle formulation for efficient miRNA delivery to acinar cells by screening a library of dendrimer-lipid nanoparticles (DLNPs) formulations for high delivery potency, low toxicity, and low immunogenicity. The ability of NP-formulated miR-216a and NPs per se to inhibit in vitro ADM will be studied on an in vitro 3-D assay. DLNPs will be engineered to target glycoprotein 2 (GP2) a cell surface marker that is exclusively expressed by normal acinar cells and those acinar cells undergoing ADM. miR-216a oligos formulated into anti-GP2 DLNPs will be evaluated for maximally tolerated dose, toxicity, biodistribution, and efficacy. The majority of therapeutic approaches for pancreatic cancer are focused on late-stage treatment, however, early preventative therapeutics that may improve the clinical outcomes of PDAC patients have not been investigated. We investigate the potential of nanotherapeutics to target pancreatic acinar cells early before the onset of PDAC. If implemented into the clinic, this therapy will allow individuals with high risk of pancreatic cancer, as identified through a biomarker, to receive administration of treatment options at an earlier stage, leading to better clinical outcomes.