High Sensitivity Molecular Ultrasound Imaging in Pancreatic Cancer

胰腺癌的高灵敏度分子超声成像

• 批准号: 9302759
• 负责人: Jeremy Dahl
• 金额: $ 20.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302759
• 关键词: Animal Model; Biological Markers; Cancer Detection; Cancer Etiology; Cessation of life; Characteristics; Clinical; Detection; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Excision; Goals; Histology; Human; Image; Imaging Techniques; Immunofluorescence Immunologic; Incidence; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Microbubbles; Molecular; Molecular Target; Noise; Operative Surgical Procedures; Outcomes Research; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase; Reference Standards; Research; Sensitivity and Specificity; Series; Signal Transduction; Source; Specificity; Stage at Diagnosis; Symptoms; System; Techniques; Testing; Time; Tissues; Transgenic Mice; Translating; Tumor stage; Ultrasonography; advanced disease; base; chronic pancreatitis; clinical development; clinical translation; clinically significant; design; diagnostic accuracy; differential expression; experience; experimental study; high risk; imaging approach; imaging capabilities; imaging system; improved; in vivo imaging system; molecular imaging; molecular marker; mouse model; pre-clinical; technique development; tumor; Animal Model; Biological Markers; Cancer Detection; Cancer Etiology; Cessation of life; Characteristics; Clinical; Detection; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Excision; Goals; Histology; Human; Image; Imaging Techniques; Immunofluorescence Immunologic; Incidence; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Microbubbles; Molecular; Molecular Target; Noise; Operative Surgical Procedures; Outcomes Research; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase; Reference Standards; Research; Sensitivity and Specificity; Series; Signal Transduction; Source; Specificity; Stage at Diagnosis; Symptoms; System; Techniques; Testing; Time; Tissues; Transgenic Mice; Translating; Tumor stage; Ultrasonography; advanced disease; base; chronic pancreatitis; clinical development; clinical translation; clinically significant; design; diagnostic accuracy; differential expression; experience; experimental study; high risk; imaging approach; imaging capabilities; imaging system; improved; in vivo imaging system; molecular imaging; molecular marker; mouse model; pre-clinical; technique development; tumor

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a very lethal form of cancer. While patient survival is highly dependent upon tumor stage, most patients already have advanced disease at the time of diagnosis due to the lack of clinical symptoms experienced by the patient until the tumor has progressed to a significant size. Also, there is a lack of both sensitive and specific imaging tests to detect early stage PDAC. Methods to detect PDAC at early stages are critically needed to improve the survival of patients with PDAC. While overall survival at diagnosis is only about 4-6 months, 30-40% of patients diagnosed at stage I disease can survive 5 years. The best currently available diagnostic test which is routinely performed in patients at high risk for PDAC is endoscopic ultrasound (EUS). However, EUS has low sensitivity and specificity and poor interobserver reliability for detecting small foci of PDAC. Combining EUS with molecular imaging capabilities (molecular CEUS) has the potential to increase our ability to detect early stage PDAC with high diagnostic accuracy. We have identified and validated a new biomarker, Thy1, which is differentially expressed in human PDAC but only minimally present in normal pancreas or chronic pancreatitis. Currently, we are developing a clinical grade Thy1-targeted contrast microbubble (MB) that allows detection of PDAC with high specificity in preclinical animal models. However, a barrier to the clinical translation of Thy1-targeted MB is the expected low concentration of targeted MB in small foci of early stage PDAC. This low concentration reduces our ability to visualize MB with conventional molecular CEUS imaging techniques because the signal to noise ratio (SNR) in tumors may not be high enough to differentiate small PDAC foci from background signal. This reduces our overall sensitivity to detect early stage PDAC. In this application, we propose to develop and test a high-sensitivity molecular CEUS imaging system using a combination of short-lag spatial coherence (SLSC) beamforming with Thy1-targeted MB. The SLSC beamforming technique utilizes the coherence characteristics of US signals to differentiate desired MB from those originating from background noise sources. This new beamforming technique will be implemented on a clinical US imaging system and tested and compared to conventional CEUS methods both in tissue mimicking phantoms as well as in a transgenic mouse model of PDAC development using Thy1-targeted MB. Because PDAC may arise in a setting of chronic pancreatitis, we will also test the SNR of molecular CEUS in PDAC on a chronic pancreatitis background. Molecular CEUS imaging signal will be correlated with histology and ex vivo quantitative immunofluorescence of Thy1 expression as reference standards. Successful completion of our research will result in a new Thy1-targeted molecular CEUS approach for early PDAC detection with improved SNR and specificity that can be further developed for clinical translation in the next phase of this research.

抽象的 胰腺导管腺癌（PDAC）是一种非常致命的癌症形式。虽然病人的生存率很高 依赖肿瘤阶段，大多数患者在诊断时已经患有晚期疾病 患者缺乏临床症状，直到肿瘤发展到显着尺寸为止。还， 缺乏敏感和特定的成像测试来检测早期PDAC。检测PDAC的方法 在早期需要至关重要的阶段来改善PDAC患者的存活率。而整体生存 诊断仅为4-6个月，在I期疾病中诊断的患者中有30-40％的诊断可以生存5年。这 当前最佳可用诊断测试通常在PDAC高风险的患者中进行 内窥镜超声（EUS）。但是，EUS具有低灵敏度和特异性，观察者间的可靠性差 用于检测PDAC的小焦点。将EUS与分子成像能力（分子CEU）相结合的具有 通过高诊断准确性来提高我们检测早期PDAC的能力的潜力。 我们已经确定并验证了一种新的生物标志物Thy1，该标志物在人类PDAC中差异表达，但 仅在正常胰腺或慢性胰腺炎中最少。目前，我们正在开发临床等级 Thy1靶向对比微泡（MB），该微泡（MB）允许在临床前动物中检测具有高特异性的PDAC 型号。但是，靶向Thy1靶向MB的临床翻译的障碍是预期的低浓度 靶向MB的早期PDAC小焦点。这种低浓度降低了我们用 传统的分子CEUS成像技术，因为肿瘤中的信号与噪声比（SNR）可能不是 足够高以将小PDAC灶与背景信号区分开。这降低了我们对 检测早期PDAC。 在此应用中，我们建议使用A开发和测试高敏性分子CEUS成像系统 短落空间相干性（SLSC）与Thy1靶向MB的结合。 SLSC 波束形成技术利用美国信号的连贯性特征将所需的MB与 源自背景噪声源的人。这种新的波束形成技术将在 临床美国成像系统并测试并与传统的CEUS方法进行了比较 幻象以及使用Thy1靶向的MB的PDAC发育的转基因小鼠模型。因为 PDAC可能是在慢性胰腺炎的环境中出现的，我们还将在A上测试PDAC中分子CEU的SNR 慢性胰腺炎背景。分子CEUS成像信号将与组织学和离体相关 THY1表达作为参考标准的定量免疫荧光。成功完成我们 研究将导致一种新的Thy1靶向分子CEU方法，以改善PDAC检测 在这项研究的下一阶段，可以进一步开发用于临床翻译的SNR和特异性。