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袭性的恶性肿瘤，预计将成为 到 2026 年，将成为癌症相关死亡的第二大原因。胰腺导管腺癌 (PDAC) 账户 超过 90% 的胰腺癌病例，总体五年生存率约为 8%，是所有胰腺癌病例中最低的 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 在初步诊断时。然而，目前由于缺乏高度稳健的药物，临床需求尚未得到满足。 早期检测 PDAC 的诊断策略。 MicroRNA (miRNA) 是小的非编码 RNA， 调节与每种人类癌症（包括 PDAC）有关的基因，因此可能是理想的生物标志物。的确， 循环游离 miRNA (cf-miRNA) 已被证明具有诊断潜力。此外，最近 发现癌细胞在称为外泌体的小细胞外囊泡中主动分泌 miRNA （exo-miRNA）彻底改变了该领域，因为肿瘤来源的外泌体货物能够识别癌症- 特定的分子标记。在上一个资助周期中，我们进行了公正的、全基因组的研究 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，以及 1) 确定了 5 个 cf-miRNA 和 8 个 exo-miRNA 组成的组，可以可靠地识别患有以下疾病的患者 早期PDAC； 2）将 cf- 和 exo-miRNA 组合成一个“转录组特征”，优于 个体生物标志物组，包括早期（I/II 期）疾病患者； 3）表明，结合 我们的 CA19-9 转录组特征进一步提高了诊断性能； 4）最重要的是， 结果表明，我们的转录组特征准确识别了 CA19-9 阴性的 PDAC 患者。 在这个竞争性续签申请中，我们将在之前的成功基础上实现 4 个具体目标。 在目标 1 中，我们将通过持续前瞻性招募 PDAC 和 癌前肿瘤（PN），包括胰腺囊性肿瘤（PCN）和家族风险， 另外还关注少数种族/族裔患者的登记和标本采集。 在目标 2 中，我们将进一步验证转录组特征并确定其在前瞻性队列中的表现 早期 PDAC 患者。在目标 3 中，我们将确定转录组学的临床意义 用于检测术前收集的血浆中是否存在高度不典型增生和浸润性癌症的特征 来自临床诊断为 PCN 的患者。在目标 4 中，我们将评估转录组签名的能力 在诊断前血浆样本的最早阶段检测 PDAC，并确定诊断前的准备时间 疾病介绍。我们提出的项目将是第一个建立临床上可行的、敏感的、特异性的、 以及用于尽早识别 PDAC 患者的强大的血液检测。如果成功的话， 该项目将推进一种简单、方便且廉价的非侵入性检测，用于常规临床实施 这将深刻改变 PDAC 的早期检测，并与其他癌症相关。

项目成果

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

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