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: 10020380
• 负责人: Ajay Goel
• 金额: $ 71.87万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020380
• 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; 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; outcome forecast; 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.

项目摘要：胰腺癌是美国成人癌症死亡的第四个主要原因，并且 到2030年将成为与癌症相关死亡的第二大原因。 测定阻碍广泛的胰腺癌诊断。显然，早期诊断程序将有所改善 胰腺导管腺癌（PDAC）患者的预后，但需要新颖的方法 发展。 microRNA（miRNA）是在肿瘤发生中暗示的小型非编码RNA 每个人类癌症，包括PDAC。重要的是，miRNA稳健，对组织中的降解具有抵抗力 和体液，使其成为无创生物标志物的理想候选者。最近发现的癌症 在小蔬菜中积极准确的特定miRNA，称为“外泌体”，带来了更多的热情 到癌症生物标志物竞技场。以前的尝试定义基于血液的miRNA生物标志物可以 区分非侵入性，早期和晚期PDAC不足或特定 由于设计的队列不当以及所使用的技术的动态范围狭窄。此外， 候选标记是非精心挑选的，研究缺乏重要的对照，并且队列 没有足够的动力或验证，或者不代表平均风险人群。这些因素卡住了 发现在转移性疾病之前可以识别无症状患者的miRNA生物标志物 开发或区分早期的射线照相pDAC与非侵入性胰腺癌 肿瘤（PNS）。在此提案中，包括下一代测序（NGS）在内的创新策略 miRNA-seq将应用于全基因组和系统发现的全面和高度特异性的发现 分析仪组织的基于血液的miRNA和匹配等离子体，可以辨别出不同阶段的入侵PDAC 和PN。提出了一种新颖而有力的新方法，以识别最高的生物标志物 敏感性和特异性，将通过前瞻性，大型，良好的样本进行验证 以下特定目标。 AIM＃1：使用使用候选细胞和外泌体miRNA生物标志物发现 PDAC，PNS，胰腺炎和正常患者的匹配组织和血浆中的小RNA-Seq 胰腺。 AIM＃2：开发一个无细胞和外泌体miRNA生物标志物面板，以区分患者 来自患有PNS或胰腺炎的人的PDAC。 AIM＃3：临床验证非侵入性的优化面板 MiRNA生物标志物（在AIM＃2中鉴定）在PDAC和PNS患者的前瞻性队列中。 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 在匹配的组织和等离子体样品中的miRNA生物标志物，并在多个特征化的多个特征中验证它们 PNS和PDAC与对照组的患者队列。如果成功的话，该提议将深刻地改变早期 - 使用非侵入性，健壮和廉价的临床测定法检测胰腺癌。