Molecular Imaging Methods for the Detection of Pancreatic Ductal Adenocarcinoma

摘要 通过我们加入胰腺癌检测联盟的提议，我们的目标是推动BioMarker 通过建立高危个人标准化生物信息库进行开发和验证工作 并评估了两种检测胰腺导管的创新分子成像方法 腺癌(PDAC)比目前可能的要早得多。我们已经在临床前演示了 靶向激酶插入结构域受体的对比增强超声(CEUS)成像研究 (KDR)可以检测到亚厘米的PDAC病变。另外，我们已经开发了一种新的PET示踪剂 选择性地与整合素αvβ6结合，这是一种在PDAC中过度表达的细胞表面受体。在这两个地方 方法，一种具有FDA IND的临床级药物存在，以允许进行首例人类临床研究 早期发现PDAC。 我们已经组建了一支经验丰富的科学团队，在胰脏病学方面拥有广泛的互补专业知识， 腹部放射学、核医学、统计学和胰腺病理学。我们的建议是高度 以几种特定的方式对标准杆做出反应。1)我们建议启动符合第三阶段探头的 胰腺囊肿患者和PDAC高危个体的生物信息库方案已确定 基于遗传风险因素或家族史。之前评估过新的生物标志物 胰腺囊肿与其他中心的合作，我们单位有经验和能力 开发和执行标准化的多中心方案，以纳入这些患者队列。2) 我们提出了两个新的分子成像试验，患者的PDAC可以手术切除。患者会 接受经腹和内窥镜下kdr靶向分子CEUS成像，整合素αvβ6 手术前进行靶向PET/CT扫描。分子CEU和PET/CT成像结果将 PDAC组织与邻近组织的组织学及定量免疫荧光的相关性 正常和慢性胰腺炎组织。3)我们还将启动两项KDR靶向分子的中试 高危PDAC患者行CEU检查。在一项研究中，我们将研究高危患者 胰腺囊肿。在另一项研究中，我们将研究因遗传风险而接受EUS筛查的患者 因素或家族史。在所有提议的试验中，将收集生物有机质以支持未来 将这些成像方法与新的循环生物标记物相结合。这些第一次的成功-- 人体试验和生物样品的系统储存将支持进一步的合作研究 早期发现PDAC。

ABSTRACT Through our proposal to join the Pancreatic Cancer Detection Consortium, we aim to drive biomarker development and validation efforts by establishing standardized bio-repositories of high risk individuals and evaluating two innovative molecular imaging approaches to detect pancreatic ductal adenocarcinoma (PDAC) much earlier than is currently possible. We have demonstrated in preclinical imaging studies that contrast-enhanced ultrasound (CEUS) targeted to a kinase insert domain receptor (KDR) can detect sub-centimeter PDAC lesions. Separately, we have developed a new PET tracer that selectively binds to integrin αvβ6, a cell surface receptor that is over-expressed in PDAC. In both approaches, a clinical grade agent with an FDA IND exists to allow first-in-human clinical studies for earlier detection of PDAC. We have formed an experienced scientific team with broad complementary expertise in pancreatology, abdominal radiology, nuclear medicine, statistics, and pancreatic pathology. Our proposal is highly responsive to the PAR in several specific ways. 1) We propose to initiate a phase 3 PRoBE-compliant bio-repository protocol of patients with pancreatic cysts and for high-risk individuals for PDAC identified based on genetic risk factors or family history. Having previously evaluated novel biomarkers in pancreatic cysts and forging collaborations with other centers, our Unit has the experience and capacity to develop and execute standardized multi-center protocols for enrolling these cohorts of patients. 2) We propose two novel molecular imaging trials patients with surgically resectable PDAC. Patients will undergo transabdominal and endoscopic KDR-targeted molecular CEUS imaging, and integrin αvβ6 targeted PET/CT scan before proceeding to surgery. Molecular CEUS and PET/CT imaging results will be correlated to histology and quantitative immunofluorescence between PDAC tissue and adjacent normal and chronic pancreatitis tissue. 3) We will also initiate 2 pilot trials of KDR-targeted molecular CEUS in patients at high risk for developing PDAC. In one study, we will study patients with high risk pancreatic cysts. In another, we will study patients undergoing EUS screening because of genetic risk factors or family history. In all the trials proposed, biospecimens will be collected to support future integration of these imaging approaches with novel circulating biomarkers. The success of these first- in-human trials, and systematic banking of biospecimens, will support further collaborative studies for earlier detection of PDAC.