Noncoding RNA Biomarkers for Noninvasive and Early Detection of Pancreatic Cancer

用于胰腺癌非侵入性早期检测的非编码 RNA 生物标志物

• 批准号: 10246989
• 负责人: Ajay Goel
• 金额: $ 144.59万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246989
• 关键词: Adult; Bioinformatics; Biological Assay; Biological Markers; Blood; Body Fluids; Cancer Diagnostics; Cancer Etiology; Cells; Cessation of life; Clinical; Cystic Neoplasm; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Disease; Early Diagnosis; Evaluation; Genes; Human; Imaging Device; Individual; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Messenger RNA; Methods; MicroRNAs; Minority; Mucinous; Mucinous Neoplasm; Neoplasms; Non-Invasive Cancer Detection; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Patients; Perception; Plasma; Population; Positron-Emission Tomography; Prognosis; Prospective cohort; Resectable; Resistance; Risk; Sampling; Sensitivity and Specificity; Serum; Small RNA; Solid; Source; Specimen; Standardization; Survival Rate; Talents; Technology; Therapeutic; Tissues; Untranslated RNA; Validation; Vesicle; base; biomarker discovery; biomarker panel; cancer biomarkers; candidate marker; clinically significant; cohort; cost effective; design; differential expression; early detection biomarkers; exosome; genome-wide; high risk; improved; innovation; method development; miRNA expression profiling; microRNA biomarkers; next generation sequencing; novel; novel strategies; pancreatic neoplasm; premalignant; prognostic; prospective; sample collection; success; transcriptome sequencing; tumorigenesis; whole genome

PROJECT SUMMARY: Pancreatic cancer is the fourth leading cause of adult cancer deaths in the U.S., and will become the second leading cause of cancer-related deaths by 2030. The lack of reliable and cost-effective assays impedes wide-spread pancreatic cancer diagnostics. Clearly, early diagnostic procedures will improve the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), but will require novel methods of development. MicroRNAs (miRNAs) are small noncoding RNAs that are implicated in the tumorigenesis of every human cancer, including PDAC. Importantly, miRNAs are robust and resistant to degradation in tissues and body fluids, making them ideal candidates as non-invasive biomarkers. The recent discovery of cancers that actively excrete specific miRNAs in small vesicles, called “exosomes”, has brought additional enthusiasm to the cancer biomarker arena. Previous attempts to define blood-based miRNA biomarkers that can discriminate between non-invasive, early-stage and late-stage PDAC were insufficiently sensitive or specific because of improperly designed cohorts and the narrow dynamic ranges of technologies used. Furthermore, candidate markers were non-comprehensively selected, studies lacked important controls, and the cohorts were insufficiently powered or validated, or did not represent the average risk population. These factors stifled the discovery of miRNA biomarkers that could identify asymptomatic patients before metastatic disease had developed, or distinguish early stage, radiographically occult PDAC from noninvasive pancreatic precancerous neoplasms (PNs). In this proposal, innovative strategies including Next Generation Sequencing (NGS)-based miRNA-Seq will be applied to the genome-wide and systematic discovery of comprehensive and highly specific blood-based miRNAs by analyzing tissues and matching plasma that discern different stages of invasive PDAC and PN. A novel and powerful new approach is being proposed to identify biomarkers with the highest sensitivity and specificity, which will be validated in a prospective, large, well-characterized samples through the following Specific Aims. Aim #1: Discover candidate cell-free and exosomal-miRNA biomarkers using small RNA-Seq in matched tissue and plasma from patients with PDAC, PNs, pancreatitis and normal pancreas. Aim #2: Develop a cell-free and exosomal-miRNA biomarker panel that distinguishes patients with PDAC from those with PNs or pancreatitis. Aim #3: Clinically validate the optimized panel of non-invasive miRNA biomarkers (identified in Aim #2) in prospective cohorts of patients with PDAC and PNs. This project is innovative as it will use NGS-based miRNA-Sequencing for discovery of cell-free and exosomal miRNA biomarkers in matched tissue and plasma samples, and validate these in multiple, well-characterized cohorts of patients with PNs and PDAC vs. controls. If successful, this proposal will profoundly transform early- detection of pancreatic cancer using a non-invasive, robust and inexpensive clinical assay.

项目概述：胰腺癌是美国成人癌症死亡的第四大原因，和 到2030年将成为癌症相关死亡的第二大原因。缺乏可靠和具有成本效益的 分析阻碍了广泛的胰腺癌诊断。显然，早期诊断程序将改善 胰腺导管腺癌（PDAC）患者的预后，但将需要新的方法， 发展microRNAs（miRNAs）是一种小的非编码RNA，与肿瘤的发生有关。 所有人类癌症包括PDAC重要的是，miRNAs在组织中是稳健的并且抵抗降解 和体液，使它们成为非侵入性生物标志物的理想候选者。最近发现的癌症 在称为“外泌体”的小泡中积极分泌特定的miRNA， 癌症生物标志物竞技场。以前试图定义基于血液的miRNA生物标志物， 非侵入性、早期和晚期PDAC之间的区分不够敏感或特异 这是因为群组设计不当以及所用技术的动态范围狭窄。此外，委员会认为， 候选标记物的选择不全面，研究缺乏重要的对照， 没有足够的把握度或验证，或不代表平均风险人群。这些因素扼杀了 miRNA生物标志物的发现可以在转移性疾病之前识别无症状患者， 发展，或区分早期阶段，影像学隐匿性PDAC与非侵袭性胰腺癌前病变 肿瘤（PN）。在这项提案中，创新战略，包括基于下一代测序（NGS） miRNA-Seq将应用于全基因组的系统性发现，全面且高度特异 通过分析组织和匹配血浆来识别侵袭性PDAC的不同阶段， 的PN。一种新颖而强大的新方法正在被提出，以确定具有最高 灵敏度和特异性，将在前瞻性、大型、充分表征的样本中进行验证， 以下具体目标。目标#1：使用基因芯片发现候选的无细胞和外泌体-miRNA生物标志物 在来自患有PDAC、PN、胰腺炎和正常的患者的匹配组织和血浆中的小RNA-Seq 胰腺目的#2：开发无细胞和外泌体-miRNA生物标志物组，以区分患有 PN或胰腺炎患者的PDAC。目标#3：临床验证非侵入性的优化面板 PDAC和PN患者前瞻性队列中的miRNA生物标志物（在目标#2中鉴定）。 该项目具有创新性，因为它将使用基于NGS的miRNA测序来发现无细胞和外泌体的 匹配的组织和血浆样本中的miRNA生物标志物，并在多个表征良好的 PN和PDAC患者队列与对照组。如果成功的话，这个提议将在早期深刻地改变- 使用非侵入性、稳健且廉价的临床测定检测胰腺癌。