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: 9279710
• 负责人: Ajay Goel
• 金额: $ 107.54万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 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/9279710
• 关键词: Adult; Alpha Cell; 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; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Patients; Perception; Plasma; Population; Positron-Emission Tomography; Premalignant; 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; microRNA biomarkers; next generation sequencing; novel; novel strategies; outcome forecast; pancreatic neoplasm; 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大原因， 到2030年将成为癌症相关死亡的第二大原因。缺乏可靠和成本效益高的 检测阻碍了广泛传播的胰腺癌诊断。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，但需要新的方法 发展。MicroRNAs(MiRNAs)是一种与肿瘤发生有关的非编码小RNA 每一种人类癌症，包括PDAC。重要的是，miRNAs很健壮，对组织中的降解具有抵抗力 和体液，使它们成为非侵入性生物标记物的理想候选者。癌症的最新发现 在被称为“外体”的小泡中主动分泌特定的miRNAs带来了额外的热情。 癌症生物标记物的舞台上。之前尝试定义基于血液的miRNA生物标记物，可以 对非侵袭性、早期和晚期PDAC的鉴别不够敏感或特异 由于设计不当的队列和使用的技术动态范围狭窄。此外， 候选标记没有得到全面的选择，研究缺乏重要的对照，而且队列 没有足够的动力或验证，或者不能代表平均风险人群。这些因素使人窒息。 MiRNA生物标记物的发现可以在转移疾病发生之前识别无症状患者 发展或区分早期、放射学上隐匿性的PDAC与非侵袭性胰腺癌前病变 肿瘤(PNS)。在该计划中，包括基于下一代测序(NGS)的创新战略 MiRNA-Seq将应用于全基因组和系统地发现全面和高度特异的 通过分析组织和匹配血浆来识别侵袭性PDAC的不同阶段的血基miRNAs 和PN。一种新的和强大的新方法正在被提出，以识别具有最高 敏感度和特异度，这将在一个预期的、大的、特征良好的样本中得到验证 以下是具体目标。目标#1：使用以下方法发现候选的无细胞和外体miRNA生物标记物 PDAC、PNS、胰腺炎及正常人配对组织和血浆中的小RNA-Seq 胰腺。目标2：开发一种无细胞和外体-miRNA生物标记物小组，以区分患者 PNS或胰腺炎患者的PDAC。目的#3：临床验证优化的无创性面板 在PDAC和PNS患者的预期队列中发现miRNA生物标志物(在AIM#2中确定)。 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切体 匹配的组织和血浆样本中的miRNA生物标记物，并在多个特征良好的情况下验证这些 PNS和PDAC患者与对照组的队列比较。如果成功，这项提议将在早期深刻地改变- 使用一种非侵入性、健壮和廉价的临床检测方法检测胰腺癌。