Early Detection of Pancreatic Cancer with Targeted Contrast-enhanced Ultrasound

靶向超声造影早期发现胰腺癌

• 批准号: 7739380
• 负责人: Juergen Karl Willmann
• 金额: $ 21.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739380
• 关键词: Acoustics; Animal Model; Binding; Biological Assay; Biology; Cancer Diagnostics; Cell Culture Techniques; Clinic; Clinical; Contrast Media; Data; Detection; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Early Diagnosis; Endoscopy; Endothelial Cells; Excision; Flow Cytometry; Foundations; Future; Gases; Goals; Histology; Human; Image; Imaging Device; Imaging Techniques; Immunofluorescence Immunologic; Ligands; Localized Disease; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Microbubbles; Modeling; Molecular; Mus; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Diseases; Patient Care; Patients; Preclinical Testing; Protocols documentation; Radiation therapy; Reference Standards; Relative (related person); Research; Research Design; Research Personnel; Research Proposals; Resolution; Screening procedure; Sensitivity and Specificity; Signal Transduction; Specificity; Staging; Survival Rate; Techniques; Testing; Time; Tissues; Transgenic Mice; Translating; Translations; Tumor Angiogenesis; Ultrasonics; Ultrasonography; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Western Blotting; Xenograft procedure; angiogenesis; chemotherapy; chronic pancreatitis; design; diagnostic accuracy; high risk; human VEGF protein; imaging modality; improved; in vivo; insight; interest; irradiation; laser capture microdissection; molecular imaging; molecular marker; mortality; mouse model; novel; novel strategies; overexpression; pancreas imaging; particle; public health relevance; receptor expression; research study; subcutaneous; tool; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Pancreatic cancer is a lethal disease. Due to its aggressiveness and our inability to detect pancreatic cancer at an early stage, the disease is often far advanced in patients at the time of diagnosis. The 5-year relative survival rate for all pancreatic cancer stages is only approximately 4%. Chemotherapy and radiotherapy have only modest benefits and surgery for localized disease is only possible in 20% of patients at the time of diagnosis. Currently early detection of pre-invasive and early invasive stages of pancreatic cancer that allows surgical resection offers our best hope for longer survival of patients with pancreatic cancer. Furthermore, early detection of pre-invasive or early stage invasive pancreatic cancer in high-risk patient groups represents a critical unmet need in the cancer diagnostic portfolio. By combining non-invasive, high-resolution ultrasound imaging with the ability to visualize and quantify markers of angiogenesis in early stage cancer at the molecular level, our overall objective is to detect pancreatic cancer at early, still curable stages and eventually decrease mortality in patients with pancreatic cancer. We hypothesize that at pre-invasive and early stage invasive pancreatic cancer, tumor angiogenic vessels [are already present and] can be visualized non-invasively with high sensitivity and specificity by targeted contrast-enhanced ultrasound (molecular ultrasound). We will use novel, clinically translatable microbubbles targeted at human vascular endothelial growth factor receptor type 2 (KDR), which has been shown to be overexpressed on angiogenic vessels in pancreatic cancer. In specific aim 1 we will test the hypothesis that tumor angiogenesis in human subcutaneous and orthotopic pancreatic cancer xenografts in mice can be visualized by molecular ultrasound using novel, clinically translatable, KDR-targeted contrast microbubbles. We will further demonstrate that the in vivo imaging signal from molecular ultrasound can be quantitatively correlated with the extent of tumor angiogenesis and expression levels of vascular endothelial growth factor receptor type 2 as assessed by ex vivo assays. In specific aim 2 we will test the hypothesis that screening with molecular ultrasound using clinically translatable, KDR-targeted microbubbles allows detection of pre-invasive and early stage invasive pancreatic cancer in a spontaneous, transgenic, mouse model of pancreatic cancer. In this aim, the optimized imaging protocol from specific aim 1 will be translated into an experimental protocol that mimics a clinical scenario wherein regular ultrasonic screening examinations for patients at high risk of developing pancreatic cancer are performed. In vivo ultrasound imaging signal will also be quantitatively correlated with the presence and magnitude of angiogenesis and VEGFR2 expression in early stage pancreatic cancer in transgenic mice as assessed by ex vivo assays. Since we are exploring a novel ultrasound contrast agent designed for future use in humans, this project will lay the groundwork for clinical translation of molecular ultrasound into patients with pancreatic cancer. In addition, this research will provide further insight into the biology of tumor angiogenesis at early stage pancreatic cancer and will bring a new approach for non-invasive molecular imaging of early stage pancreatic cancer to othe investigators with similar research interests. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a lethal disease with early detection currently offering the best hope to improve patient survival. Ultrasound, often combined with endoscopy, is among the primary imaging approaches in patients with suspected pancreatic disease. However, ultrasound is not sensitive and specific enough to detect pancreatic cancer at an early stage. In this research application, we develop and test a modified ultrasound imaging technique that can visualize markers at the molecular level that are present at very early stages of pancreatic cancer. We use gas-filled microbubbles as contrast agents to visualize preinvasive and early stage invasive pancreatic cancer in different murine models of pancreatic cancer. The contrast microbubbles used in our research are designed for a future use in humans. Therefore, this project will lay the foundation for a use of molecular ultrasound in patients with pancreatic cancer. Following successful outcome with our current study, we anticipate rapid translation of this technique into the clinic to expand patient survival and improve patient care by diagnosing this deadly disease much earlier.

描述（由申请人提供）：胰腺癌是一种致命疾病。由于胰腺癌的侵袭性以及我们无法在早期发现胰腺癌，因此在诊断时患者的疾病通常已处于晚期。所有胰腺癌分期的 5 年相对生存率仅为 4% 左右。化疗和放疗的疗效有限，诊断时只有 20% 的患者可以针对局部疾病进行手术。目前，早期检测胰腺癌的浸润前和早期浸润阶段并允许手术切除为我们延长胰腺癌患者的生存期提供了最大的希望。此外，高危患者群体中浸润前或早期浸润性胰腺癌的早期检测代表了癌症诊断组合中未满足的关键需求。通过将非侵入性高分辨率超声成像与在分子水平上可视化和量化早期癌症血管生成标志物的能力相结合，我们的总体目标是在早期、仍可治愈的阶段检测出胰腺癌，并最终降低胰腺癌患者的死亡率。我们假设，在浸润前和早期浸润性胰腺癌中，肿瘤血管生成血管[已经存在，并且]可以通过靶向对比增强超声（分子超声）以高灵敏度和特异性非侵入性地可视化。我们将使用针对人血管内皮生长因子受体 2 型 (KDR) 的新型临床可翻译微泡，该受体已被证明在胰腺癌的血管生成血管中过度表达。在具体目标 1 中，我们将测试以下假设：可以使用新型、可临床翻译的 KDR 靶向对比微泡通过分子超声来可视化人类皮下和小鼠原位胰腺癌异种移植物中的肿瘤血管生成。我们将进一步证明分子超声的体内成像信号可以与肿瘤血管生成的程度和通过离体测定评估的2型血管内皮生长因子受体的表达水平定量相关。在具体目标 2 中，我们将测试以下假设：使用临床可转化的 KDR 靶向微泡进行分子超声筛查，可以在自发性转基因小鼠胰腺癌模型中检测浸润前和早期浸润性胰腺癌。在此目标中，特定目标 1 的优化成像方案将转化为模拟临床场景的实验方案，其中对胰腺癌高风险患者进行定期超声筛查检查。体内超声成像信号也将与转基因小鼠早期胰腺癌中血管生成和 VEGFR2 表达的存在和程度定量相关，如通过离体测定评估的那样。由于我们正在探索一种专为未来在人类中使用而设计的新型超声造影剂，因此该项目将为分子超声临床转化到胰腺癌患者中奠定基础。此外，这项研究将进一步深入了解早期胰腺癌肿瘤血管生成的生物学，并将为其他具有类似研究兴趣的研究者带来早期胰腺癌非侵入性分子成像的新方法。公共卫生相关性：胰腺癌是一种致命疾病，目前早期发现为提高患者生存率提供了最大希望。超声检查通常与内窥镜检查相结合，是疑似胰腺疾病患者的主要成像方法之一。然而，超声波的敏感性和特异性不足以在早期发现胰腺癌。在这项研究应用中，我们开发并测试了一种改进的超声成像技术，该技术可以在分子水平上可视化胰腺癌早期阶段的标记物。我们使用充气微泡作为造影剂来可视化不同胰腺癌小鼠模型中的浸润前和早期浸润性胰腺癌。我们研究中使用的对比微泡是为未来在人类中的使用而设计的。因此，该项目将为分子超声在胰腺癌患者中的应用奠定基础。在我们当前的研究取得成功之后，我们预计这项技术会迅速转化为临床，通过更早地诊断这种致命疾病来扩大患者的生存率并改善患者的护理。