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，它将成为癌症相关死亡的第二大原因。缺乏可靠且具有成本效益的方法 显然，早期诊断程序将会得到改善。 胰腺导管腺癌 (PDAC) 患者的预后，但需要新的方法 MicroRNA (miRNA) 是与肿瘤发生有关的小非编码 RNA。 每种人类癌症，包括 PDAC 重要的是，miRNA 非常强大并且能够抵抗组织中的降解。 和体液，使它们成为非侵入性生物标志物的理想候选者。 主动分泌小囊泡（称为“外泌体”）中的特定 miRNA 带来了额外的热情 之前尝试定义基于血液的 miRNA 生物标志物。 区分非侵入性、早期和晚期 PDAC 的敏感性或特异性不够 由于队列设计不当和所使用技术的动态范围狭窄。 候选标记物的选择不全面，研究缺乏重要的对照，并且队列 动力或验证不足，或者不代表平均风险人群。 miRNA 生物标志物的发现可以在转移性疾病发生之前识别无症状患者 发展或区分早期、放射学隐匿性 PDAC 与非侵袭性胰腺癌前期 在此提案中，创新策略包括基于下一代测序（NGS）的策略。 miRNA-Seq将应用于全基因组、系统性的全面、高度特异性的发现 通过分析组织和匹配血浆来识别基于血液的 miRNA，以识别侵入性 PDAC 的不同阶段 正在提出一种新颖且强大的新方法来识别具有最高值的生物标志物。 敏感性和特异性，将通过前瞻性、大型、特征良好的样本进行验证 以下具体目标#1：使用发现候选的无细胞和外泌体 miRNA 生物标志物。 PDAC、PN、胰腺炎和正常患者的匹配组织和血浆中的小 RNA 测序 目标#2：开发一种无细胞和外泌体 miRNA 生物标志物组来区分胰腺疾病患者。 来自 PN 或胰腺炎患者的 PDAC 目标 3：临床验证优化的非侵入性组合。 PDAC 和 PN 患者前瞻性队列中的 miRNA 生物标志物（目标 #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泌体 匹配的组织和血浆样本中的 miRNA 生物标志物，并在多个、充分表征的样本中验证这些生物标志物 PN 和 PDAC 患者与对照患者的队列如果成功，这一提议将深刻改变早期的情况。 使用非侵入性、稳健且廉价的临床检测来检测胰腺癌。