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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要胰腺导管腺癌（PDAC）目前是美国第三大致命癌症。目前在美国癌症相关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癌症，仅次于肺癌的胰腺癌预后不良，部分原因在于诊断已属晚期。被诊断患有胰腺癌的患者通常会在发病后一年或更短的时间内死于该病胰腺癌的新发病率和死亡率几乎相同，强调了这一事实。几乎所有被诊断患有胰腺癌的患者最终都会死于这种疾病。制定改善胰腺癌早期诊断和治疗的策略至关重要。小鼠，胰腺癌前驱病变 – 胰腺上皮内肿瘤或 PanIN 之前是腺泡导管化生 (ADM) 的过程中 microRNA (miRNA) 是一类小的非编码 RNA。我们之前的研究表明 miRNA 具有抑制肿瘤的作用。在 MIR217 宿主基因内编码，即 miR-216a、-216b 和 -217，这些 miRNA 富含胰腺。主要在胰腺腺泡中表达，但在癌前阶段（ADM 和 PanIN）和 PDAC 基于这些发现，我们将 miR-216a 恢复到了通过腺泡细胞靶向纳米粒子（NP）对胰腺进行治疗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聚合物-脂质库，纳米颗粒制剂可有效地将 miRNA 递送至腺泡细胞纳米颗粒（DLNP）制剂具有高递送效力、低毒性和低免疫原性的能力。将通过体外 3-D 测定研究 NP 配制的 miR-216a 和 NP 本身抑制体外 ADM 的作用。 DLNP 将被设计为靶向糖蛋白 2 (GP2)，这是一种细胞表面标记物，仅由正常腺泡细胞和那些经历 ADM 的腺泡细胞配制为抗 GP2 DLNP。将评估最大耐受剂量、毒性、生物分布和功效。大多数胰腺癌的治疗方法都集中在晚期治疗，然而，可能改善 PDAC 患者临床结果的早期预防性治疗尚未得到证实我们研究了纳米疗法在早期靶向胰腺腺泡细胞的潜力。如果在临床上实施，这种疗法将有助于患有胰腺癌的高危人群。通过生物标志物识别的癌症，在早期阶段接受治疗方案的管理，从而获得更好的临床结果。