Distinguishing Pancreatic Cancer from Benign Pancreatic Disease using Nanoparticle-based Biomarkers

使用基于纳米颗粒的生物标志物区分胰腺癌和良性胰腺疾病

• 批准号: 10542739
• 负责人: Stuart Duncan Ibsen
• 金额: $ 46.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542739
• 关键词: Address; Benign; Biological Markers; Blinded; Blood; Blood Plasma Volume; Blood Tests; CA-19-9 Antigen; Cancer Detection; Cancer Patient; Categories; Circulation; Clinic; Clinical; Cohort Studies; Collection; Cyst; Cytolysis; Data; Dependence; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Endoscopic Ultrasonography; Evaluation; Financial cost; Fine needle aspiration biopsy; Frequencies; Health; High Resolution Computed Tomography; Hypoxia; Image; Imaging Techniques; Individual; Investigation; Knowledge; Label; Lesion; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Microelectrodes; Microfluidic Microchips; Monitor; Necrosis; Organelles; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Patients; Plasma; Probability; Procedures; Proteins; Recovery; Research; Research Personnel; Retrospective cohort; Risk; Sampling; Source; Symptoms; Techniques; Technology; Time; Translating; Tumor-Derived; Validation; Work; acute pancreatitis; biomarker panel; blood-based biomarker; cancer type; candidate marker; clinical development; cost; early detection biomarkers; efficacy evaluation; exosome; extracellular vesicles; follow-up; mortality; nanoparticle; novel; pancreatic cancer patients; particle; patient stratification; premalignant; protein biomarkers; screening; technology platform; tumor

Project Summary This project evaluates the efficacy of using biomarkers carried by tumor-derived exosomes and other organelle- derived extracellular vesicles to differentiate patients with pancreatic cancer from patients with benign pancreatic disease. We will use high conductance dielectrophoresis-based technology to simultaneously recover different types of these cancer-derived nanoparticles from individual samples of volume limited patient plasma. This will enable access to volume restricted early stage cancer samples. This research will generate new knowledge supporting the development of a nanoparticle-based biomarker panel for early and late stage pancreatic cancer detection and will support the rationale to bring nanoparticle-based diagnostics to the clinical setting. Pancreatic cysts are coincidently discovered with increasing frequency as the use of high resolution CT and MRI imaging increases, with up to 9.3% of patients having an asymptomatic cyst. An invasive endoscopic ultrasound guided fine needle aspiration biopsy (EUS/FNA) is traditionally used to determine if the cyst is pancreatic ductal adenocarcinoma (PDAC). This has a high financial cost and associated health risk where 1/100 patients will develop acute pancreatitis and 1/10 of these patients will die. Currently 60-76% of patients that undergo EUS/FNA do not have pancreatic cancer. This signifies the unmet clinical need to develop a blood test to stratify patients with pancreatic cysts into categories of high-probability and low-probability for having PDAC, where high-probability would benefit from the EUS/FNA. Currently, no blood based PDAC biomarkers exist. Tumor- derived nanoparticles offer a new source of potential PDAC related biomarkers. The challenge is that traditional nanoparticle recovery methods for each nanoparticle type require plasma volumes that are too large to be supported with currently available PDAC patient plasma samples. Our preliminary data now suggest that high conductance dielectrophoresis (DEP) techniques can recover sufficient amounts of nanoparticle derived biomarkers to detect precancerous lesions as well as differentiate early and late stage PDAC from controls and requires only 30 µl of plasma. Each Aim will translate our DEP validation of individual biomarkers into a panel that will be evaluated in a blinded cohort study consisting of patients with PDAC and benign pancreatic disease. We focus Aim 1 on particles actively released by tumors, and Aim 2 on different cellular organelle fragments. Aim 3 evaluates these biomarkers, and five from our preliminary data, on stage 1 and 2 PDAC samples. The significance of this research is that the knowledge generated will lead to potential validation of a panel of nanoparticle-associated biomarkers capable of differentiating PDAC from benign pancreatic disease. The research proposed here may ultimately support the rationale for the clinical development of a nanoparticle-based diagnostic blood test to identify patients with pancreatic cysts that would benefit from the EUS/FNA procedure.

项目摘要 该项目评估了使用肿瘤源性外泌体和其他细胞器携带的生物标志物的有效性， 衍生的细胞外囊泡，以区分胰腺癌患者和良性胰腺癌患者。 疾病我们将使用高电导率双稳态技术， 这些癌症衍生的纳米颗粒的类型来自体积有限的患者血浆的个体样品。这将 能够获得体积受限的早期癌症样本。这项研究将产生新的知识 支持开发用于早期和晚期胰腺癌的基于纳米颗粒的生物标志物组 检测，并将支持将基于纳米颗粒的诊断带到临床环境的基本原理。 随着高分辨率CT和MRI的应用，胰腺囊肿的发现率越来越高 影像学检查结果显示，高达9.3%的患者有无症状的囊肿。有创超声内镜 传统上使用引导细针穿刺活检（EUS/FNA）来确定囊肿是否为胰腺导管 腺癌（PDAC）。这具有很高的财务成本和相关的健康风险，其中1/100的患者将 发生急性胰腺炎，这些患者中有1/10会死亡。目前，60-76%的患者接受 EUS/FNA没有胰腺癌。这意味着开发一种血液测试来分层 胰腺囊肿患者分为高概率和低概率PDAC，其中 高概率将受益于EUS/FNA。目前，不存在基于血液的PDAC生物标志物。肿瘤- 衍生的纳米颗粒提供了潜在的PDAC相关生物标志物的新来源。挑战在于传统的 用于每种纳米颗粒类型的纳米颗粒回收方法需要太大的等离子体体积， 支持当前可用的PDAC患者血浆样本。我们的初步数据显示， 电导介电电泳（DEP）技术可以回收足够量的纳米颗粒衍生物， 检测癌前病变以及区分早期和晚期PDAC与对照组的生物标志物， 只需要30微升血浆。每个Aim将把我们对单个生物标志物的DEP验证转化为一个面板 将在由PDAC和良性胰腺疾病患者组成的盲态队列研究中进行评估。 我们将目标1集中在肿瘤主动释放的颗粒上，目标2集中在不同的细胞器片段上。 目的3评估这些生物标志物，以及来自我们初步数据的5个，在第1阶段和第2阶段PDAC样品上。 这项研究的意义在于，所产生的知识将导致一个小组的潜在验证， 纳米颗粒相关的生物标志物能够区分PDAC与良性胰腺疾病。的 这里提出的研究可能最终支持基于纳米颗粒的临床开发的基本原理。 诊断性血液检查，以确定胰腺囊肿患者将受益于EUS/FNA程序。