Exosome-based microRNA biomarkers for Non-invasive and Early Detection of Pancreatic Cancer

基于外泌体的 microRNA 生物标志物用于胰腺癌的非侵入性早期检测

• 批准号: 10722729
• 负责人: Ajay Goel
• 金额: $ 92.39万
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722729
• 关键词: Address; Area Under Curve; Bioinformatics; Biological Assay; Biological Markers; Blood; CA-19-9 Antigen; Cancer Etiology; Cells; Cessation of life; Clinical; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diagnostic Specificity; Disease; Early Diagnosis; Enrollment; Excretory function; Funding; Genes; High grade dysplasia; Human; Imaging Device; Individual; Institution; Intellectual Property; Intraepithelial Neoplasia; Lead; Legal patent; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Messenger RNA; MicroRNAs; Monitor; Neoplasms; Non-Invasive Detection; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic cystic neoplasia; Participant; Patients; Performance; Plasma; Prospective cohort; Resectable; Risk; Screening for cancer; Serology; Serum; Specificity; Specimen; Survival Rate; Time; Tumor Markers; Tumor-Derived; Untranslated RNA; Validation; advanced disease; biobank; biomarker discovery; biomarker panel; biomarker validation; cancer biomarkers; cancer cell; cancer diagnosis; cancer invasiveness; clinical diagnosis; clinical implementation; clinical translation; clinically significant; cohort; diagnostic strategy; ethnic diversity; ethnic minority population; exosome; extracellular vesicles; genome-wide; high risk; improved; machine learning algorithm; miRNA expression profiling; microRNA biomarkers; molecular marker; pancreatic cancer patients; participant enrollment; premalignant; prognostic; prospective; racial diversity; racial minority population; response; sample collection; success; transcriptomics; tumor

PROJECT SUMMARY: Pancreatic cancer is a highly aggressive malignancy that is estimated to become the second leading cause of cancer-related deaths by 2026. Pancreatic ductal adenocarcinoma (PDAC) accounts for >90% of all pancreatic cancer cases and has an overall five-year survival rate of ~8%, the lowest among the major cancers. In PDAC, only 15–20% of patients present with localized, resectable, potentially curable tumors at initial diagnosis. However, currently there is an unmet clinical need for the lack of availability of highly robust diagnostic strategies for the early detection of PDAC. MicroRNAs (miRNAs) are small non-coding RNAs that regulate genes implicated in every human cancer, including PDAC, and may thus be ideal biomarkers. Indeed, circulating cell-free miRNAs (cf-miRNAs) have been shown to have diagnostic potential. Furthermore, the recent discovery that cancer cells actively excrete miRNAs in small extracellular vesicles called exosomes (exo-miRNAs) has revolutionized the field, as tumor-derived exosomal cargo enables the identification of cancer- specific molecular markers. During the previous cycle of funding, we performed unbiased and genome-wide sequencing-based miRNA profiling approaches, together with rigorous bioinformatics and machine-learning algorithms, and 1) identified panels of 5 cf-miRNAs and 8 exo-miRNAs that could robustly identify patients with early-stage PDAC; 2) combined the cf- and exo-miRNAs into a “transcriptomic signature” that was superior to individual biomarker panels, including patients with early-stage (stage I/II) disease; 3) showed that combining our transcriptomic signature with CA19-9 further improved diagnostic performance; and 4) most importantly, showed that our transcriptomic signature accurately identified patients with PDAC who were CA19-9-negative. In this competing renewal application, we will build upon our previous success by undertaking 4 specific aims. In Aim 1, we will expand our biorepository via continued prospective enrollment of patients with PDAC and precancerous neoplasms (PNs), including those with pancreatic cystic neoplasms (PCNs) and familial risk, with an additional focus on enrollment of and specimen collection from patients of racial/ethnic minority populations. In Aim 2, we will further validate the transcriptomic signature and establish its performance in prospective cohorts of patients with early-stage PDAC. In Aim 3, we will determine the clinical significance of our transcriptomic signature to detect the presence of high-grade dysplasia and invasive cancer in pre-operative plasma collected from patients clinically diagnosed as PCNs. In Aim 4, we will evaluate the ability of our transcriptomic signature to detect PDAC at its earliest stages in pre-diagnosis plasma specimens and to determine lead time before disease presentation. Our proposed project will be the first to establish a clinically feasible, sensitive, specific, and robust blood-based assay for identifying patients with PDAC at the earliest possible stages. If successful, this project will advance a simple, facile, and inexpensive non-invasive assay for routine clinical implementation that will profoundly transform the early detection of PDAC, with relevance for other cancers.

项目摘要：胰腺癌是一种高度侵略性的恶性肿瘤，估计成为 到2026年，与癌症相关死亡的第二大原因。胰腺导管腺癌（PDAC）帐户 对于所有胰腺癌病例中的90％> 90％，总体五年生存率约为8％，是最低的 主要癌症。在PDAC中，只有15-20％的患者患有局部，可切除，可能治愈的肿瘤 在最初的诊断中。但是，目前对缺乏高度鲁棒性的临床需求未满足 早期检测PDAC的诊断策略。 microRNA（miRNA）是小型非编码RNA 调节包括PDAC在内的每个人类癌症中实施的基因，因此可能是理想的生物标志物。的确， 循环无细胞的miRNA（CF-MIRNA）已显示具有诊断潜力。此外，最近 发现癌细胞在小细胞外蔬菜中积极出色的miRNA，称为外泌体 （Exo-MiRNA）彻底改变了该领域，因为肿瘤衍生的外泌体货物可以鉴定癌症 - 特定的分子标记。在上一个资金周期中，我们进行了公正和全基因组的偏见 基于测序的miRNA分析方法，以及严格的生物信息学和机器学习 算法和1）确定了5个CF-MIRNA和8个外型肌的面板，这些面板可以牢固地识别患有患者的患者 早期PDAC； 2）将CF-和EXO-MIRNA合并为“转录组签名”，优于优越 单个生物标志物面板，包括早期（I/II期）疾病的患者； 3）表明结合 我们具有CA19-9的转录组签名进一步提高了诊断性能； 4）最重要的是， 表明我们的转录组签名准确地鉴定出患有CA19-9阴性的PDAC患者。 在此竞争性续约应用中，我们将通过实现4个特定目标来建立我们以前的成功。 在AIM 1中，我们将通过持续的PDAC患者和 癌前肿瘤（PNS），包括患有胰腺囊性肿瘤（PCN）和家庭风险的肿瘤肿瘤（PNS） 额外的重点是从种族/族裔少数族裔人群的患者的标本收集和标本收集。 在AIM 2中，我们将进一步验证转录组签名并在潜在队列中建立其性能 早期PDAC患者的患者。在AIM 3中，我们将确定转录组的临床意义 签名以检测术前血浆中高级发育不良和侵入性癌症的存在 来自临床诊断为PCN的患者。在AIM 4中，我们将评估转录组签名的能力 在诊断前血浆标本中最早检测PDAC，并确定提前时间 疾病表现。我们提出的项目将是第一个建立临床可行，敏感，特定的项目的项目 以及最早可能识别PDAC患者的鲁棒基于血液的评估。如果成功， 该项目将推进一个简单，便捷且廉价的非侵入性测定法，以进行常规临床实施 这将深刻地改变PDAC的早期发现，并与其他癌症有关。

项目成果

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

• DOI: 10.1053/j.gastro.2022.06.090
• 发表时间: 2022-11
• 期刊: Gastroenterology
• 影响因子: 29.4

Role of 3D Volumetric and Perfusion Imaging for Detecting Early Changes in Pancreatic Adenocarcinoma.

• DOI: 10.3389/fonc.2021.678617
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Rahmanuddin S;Korn R;Cridebring D;Borazanci E;Brase J;Boswell W;Jamil A;Cai W;Sabir A;Motarjem P;Koay E;Mitra A;Goel A;Ho J;Chung V;Von Hoff DD
• 通讯作者: Von Hoff DD