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: 10363335
• 负责人: Stuart Duncan Ibsen
• 金额: $ 47.17万
• 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/10363335
• 关键词: Address; Benign; Biological Markers; Blinded; Blood; Blood Circulation; Blood Plasma Volume; Blood Tests; CA-19-9 Antigen; Cancer Detection; Cancer Patient; Categories; 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; base; 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; 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 该项目评估了使用由肿瘤衍生的外泌体和其他细胞器携带的生物标志物的效率 衍生的细胞外蔬菜使胰腺癌患者与良性胰腺患者区分开 疾病。我们将使用高电导电介摄取技术来简单地恢复不同的不同 这些癌症衍生的纳米颗粒的类型来自体积的单个样品有限的患者血浆。这会 使能够访问限制的早期癌症样本。这项研究将产生新知识 支持开发基于纳米颗粒的生物标志物面板，用于早期和晚期胰腺癌 检测并将支持将基于纳米颗粒的诊断诊断到临床环境的基本原理。 随着使用高分辨率CT和MRI的使用，胰腺囊肿偶然地以越来越多的频率发现 成像增加，最多9.3％的患有无症状囊肿的患者。侵入性内窥镜超声 传统上使用指导细针吸入活检（EUS/FNA）来确定囊肿是否为胰管导管 腺癌（PDAC）。这具有高财务成本和相关的健康风险，其中1/100名患者将 发展急性胰腺炎，其中1/10例将死亡。目前有60-76％的患者 EUS/FNA没有胰腺癌。这表示未满足的临床需要开发血液检查以进行分层 胰腺囊肿的患者分为具有PDAC的高概率和低概率的类别 高概率将从EUS/FNA中受益。目前，没有基于血液的PDAC生物标志物。瘤- 衍生的纳米颗粒提供了潜在的与PDAC相关的生物标志物的新来源。挑战是传统 每种纳米颗粒类型的纳米颗粒恢复方法都需要太大的等离子体体积 支持当前可用的PDAC患者血浆样品。我们的初步数据现在表明很高 电导介电性（DEP）技术可以恢复足够数量的纳米颗粒。 生物标志物检测癌前病变，并将早期和晚期PDAC与对照组区分开 仅需要30 µL血浆。每个目标都会将我们对单个生物标志物的深度验证转化为面板 这将在一项盲目的队列研究中进行评估，该研究由PDAC和良性胰腺疾病患者组成。 我们将目标1集中在肿瘤积极释放的颗粒上，而瞄准2在不同的细胞细胞器片段上。 AIM 3在第1阶段和第2阶段的PDAC样品上评估了这些生物标志物，并从我们的初步数据中评估了五个。 这项研究的意义在于，产生的知识将导致一组小组的潜在验证 纳米颗粒相关的生物标志物，能够将PDAC与良性胰腺疾病区分开。这 这里提出的研究最终可能支持基于纳米颗粒的临床发展的基本原理 诊断血液检查以鉴定患有胰腺囊肿的患者，这些患者将受益于EUS/FNA程序。