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，我们的目标是推动生物标志物 通过建立高风险个人的标准化生物储存库， 并评估两种创新的分子成像方法来检测胰腺导管 腺癌（PDAC）比目前可能早得多。我们已经在临床前研究中证明， 对比增强超声（CEUS）靶向激酶插入结构域受体的成像研究 (KDR)可以检测到亚厘米的PDAC病变。另外，我们开发了一种新的PET示踪剂， 选择性结合整联蛋白αvβ6，这是一种在PDAC中过表达的细胞表面受体。无论是 方法，具有FDA IND的临床级药物存在，以允许首次在人体内进行临床研究， 早期检测PDAC。 我们组建了一支经验丰富的科学团队，在胰腺病学方面具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 以几种特定方式响应PAR。1)我们建议启动第三阶段符合PRoBE的 胰腺囊肿患者和PDAC高风险个体的生物储存方案已确定 根据遗传风险因素或家族史。先前评估了新的生物标志物， 胰腺囊肿和锻造与其他中心的合作，我们的单位有经验和能力 制定和执行标准化的多中心方案，以招募这些患者队列。（二） 我们提出了两个新的分子影像学试验患者手术切除PDAC。患者将 接受经腹和内镜KDR靶向分子CEUS成像，整合素αvβ6 在进行手术前进行PET/CT扫描。分子CEUS和PET/CT成像结果将 与PDAC组织和相邻组织之间的组织学和定量免疫荧光相关 正常和慢性胰腺炎组织。3)我们还将启动2项KDR靶向分子药物的中试试验， 发生PDAC的高风险患者的CEUS。在一项研究中，我们将研究高风险患者， 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。在所有拟议的试验中，将收集生物标本，以支持未来的研究。 这些成像方法与新的循环生物标志物的整合。这些第一次的成功- 人体试验和生物标本的系统库，将支持进一步的合作研究， 早期检测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.