R21 MPI microRNA directed therapy for treating early stage pancreatic cancer

R21 MPI microRNA 定向疗法治疗早期胰腺癌

• 批准号: 10577609
• 负责人: THOMAS D. SCHMITTGEN
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577609
• 关键词: 3' Untranslated Regions; 3-Dimensional; Acinar Cell; Acinus organ component; Acute; Age; Attenuated; Binding Sites; Biodistribution; Biological Assay; Biological Markers; Blood; Body Temperature Changes; Body Weight; Caerulein; Cell Line; Cell surface; Cessation of life; Chemotherapy and/or radiation; Chronic; Clinic; Clinical; Colorectal Cancer; Data; Death Rate; Dendrimers; Development; Diagnosis; Disease; Dose; Duct (organ) structure; Early Diagnosis; Early treatment; Engineering; Epigenetic Process; Epithelium; Event; Formulation; Genes; Glycoproteins; Histology; Immunotherapy; In Vitro; Incidence; Individual; Intraepithelial Neoplasia; KPC model; KRASG12D; Knockout Mice; Lesion; Libraries; Luc Gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mesenchymal; Metaplasia; Methods; MicroRNAs; Mus; Oligonucleotides; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Process; Prognosis; Prophylactic treatment; Publishing; Quantitative Reverse Transcriptase PCR; Repression; Role; Testing; Therapeutic; Toxic effect; Transfection; Treatment Effectiveness; Tumor Suppression; United States; Untranslated RNA; acute pancreatitis; arm; cancer initiation; cancer therapy; effective therapy; efficacy study; high risk; immunogenicity; improved; in vivo evaluation; lipid nanoparticle; microRNA delivery; nanoformulation; nanoparticle; nanoparticle delivery; nanotherapeutic; new therapeutic target; novel; premalignant; restoration; screening; tumor; tumorigenesis; vector

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.

项目摘要 胰腺导管腺癌(PDAC)是目前美国第三大致命性癌症。它是 目前在美国与癌症相关的死亡人数中排名第三，到本十年末， 胰腺癌预计将超过结直肠癌，成为美国第二大致命性癌症， 仅次于肺癌。胰腺癌预后较差的部分原因是诊断较晚。 被诊断为胰腺癌的患者通常在最初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，强调了这样一个事实 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， 制定改进胰腺癌早期诊断和治疗的策略至关重要。在……里面 小鼠，胰腺癌前驱病变-胰腺上皮内肿瘤或Panins之前有 腺泡导管化生(ADM)过程。MicroRNA(MiRNA)是一类小的非编码RNA， 从表观遗传学上调节这些过程。我们先前的研究表明miRNAs的肿瘤抑制作用 编码在MIR217宿主基因内，即miR-216a、-216b和-217。这些miRNAs富含胰腺 在胰腺腺泡中主要表达，但在癌前阶段(ADM和 Panin)和PDAC中。基于这些发现，我们假设miR-216a恢复到 胰腺通过腺泡细胞靶向纳米颗粒(NPs)可以将早期癌症病变转移到 腺泡状态，减少PANIN和PDAC的形成。为了检验我们的假设，我们将优化 通过筛选树枝状大分子脂类文库高效地将miRNA输送到腺泡细胞的纳米制剂 纳米粒(DLNPs)制剂，用于高递送效力、低毒性和低免疫原性。一种能力 NP配方的miR-216a和NPs本身在体外抑制ADM的作用将在体外三维实验中进行研究。 DLNPs将被设计成靶向糖蛋白2(GP2)，这是一种细胞表面标记，由 正常的腺泡细胞和经历ADM的腺泡细胞。制备抗GP2 DLNPs的miR-216a寡核苷酸 将评估最大耐受量、毒性、生物分布和疗效。 然而，大多数胰腺癌的治疗方法都集中在晚期治疗上， 可能改善PDAC患者临床结局的早期预防性治疗尚未得到 调查过了。我们研究了纳米疗法在早期靶向胰腺腺泡细胞的可能性。 动脉导管未闭发作。如果将这种疗法应用于临床，将允许胰腺高危个体 通过生物标记物识别的癌症，在早期阶段接受治疗选项的管理， 从而带来更好的临床结果。