Early Detection of Pancreatic Cancer with Targeted Contrast-enhanced Ultrasound

描述（申请人提供）：胰腺癌是一种致命疾病。由于其侵袭性和我们无法在早期发现胰腺癌，在诊断时，这种疾病通常在患者身上已经很晚期了。所有胰腺癌分期的5年相对生存率仅约为4%。化疗和放疗只有适度的益处，在诊断时，只有20%的患者可以对局部疾病进行手术治疗。目前，早期发现浸润前和早期浸润期的胰腺癌，允许手术切除，为胰腺癌患者延长生存期提供了最大的希望。此外，在高风险患者群体中早期检测浸润前或早期浸润性胰腺癌是癌症诊断组合中一个关键的未满足的需求。通过将无创、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、仍可治愈的阶段发现胰腺癌，并最终降低胰腺癌患者的死亡率。我们假设，在侵袭前和早期浸润性胰腺癌中，肿瘤血管生成血管已经存在，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。我们将使用新的、临床可翻译的微泡靶向人类血管内皮生长因子受体2型（KDR），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，我们将检验假设，即使用新型的、临床可翻译的、kdr靶向造影剂微泡，可以通过分子超声观察小鼠皮下和原位胰腺癌异种移植物的肿瘤血管生成。我们将进一步证明，分子超声的体内成像信号可以定量地与肿瘤血管生成的程度和血管内皮生长因子受体2型的表达水平相关。在特定的目标2中，我们将检验假设，即使用临床可翻译的，kdr靶向的微泡进行分子超声筛查，可以在自发的，转基因的胰腺癌小鼠模型中检测侵袭前和早期侵袭性胰腺癌。在这个目标中，来自特定目标1的优化成像方案将转化为模拟临床场景的实验方案，其中对患胰腺癌的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定量地与转基因小鼠早期胰腺癌血管生成和VEGFR2表达的存在和大小相关，通过离体试验评估。由于我们正在探索一种用于人类的新型超声造影剂，该项目将为分子超声在胰腺癌患者中的临床应用奠定基础。此外，本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机制，并为其他具有类似研究兴趣的研究者提供早期胰腺癌无创分子成像的新途径。公共卫生相关性：胰腺癌是一种致命疾病，早期发现是目前提高患者生存率的最大希望。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影像学检查方法之一。然而，超声在早期发现胰腺癌的灵敏度和特异性不够。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存在于胰腺癌早期阶段的标志物。我们使用充满气体的微泡作为造影剂，在不同的小鼠胰腺癌模型中观察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将来在人类中使用而设计的。因此，本项目将为分子超声在胰腺癌患者中的应用奠定基础。随着我们目前研究的成功结果，我们期待这项技术迅速转化为临床，通过更早地诊断这种致命疾病来扩大患者的生存和改善患者护理。

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.