Peptide-based targeted molecular imaging for early detection in pancreatic cancer

胰腺导管腺癌(PDAC)的主要挑战之一是鉴别， 开发和验证使早期检测成为可能的新型分子标记和成像探针 为治疗方案提供合理的指导。我们提出了整合素亚型αvβ6作为一种新的 结合非侵入性多肽的分子成像标记的进一步开发和验证 用于体内检测疾病进展的分子成像策略。αvβ6是一种上皮细胞特异性细胞 在健康的成人上皮中检测不到的表面受体，但在很大范围内显著上调 上皮源性癌症。这种受体通常定位于肿瘤的侵袭性前沿，并发挥关键作用。 在侵袭和转移方面。αvβ6最初在胰腺癌中被发现，大多数人类 被测试的PDAC样本从IHC获得最高分数。PI开发了一款αvβ6-Directed 18F-αvβ6-结合肽(18F-αvβ6-BP)，对αvβ6具有高亲和力和选择性 整合素在荷瘤小鼠和非人灵长类动物中表现出良好的药代动力学。 FDA最近批准了进行首个人体研究的批准。 U01的总体目标是验证αvβ6整合素作为非侵入性分子成像靶点用于 ~(18)F-α与β~(6-BP)在正电子发射计算机断层显像中的早期诊断我们的三个目标将在这五年内并行实现 求婚。目的1)研究α-v-β-6在人胰腺组织中的表达。 B)我们将评估αvβ6在小鼠胰腺癌进展模型中的非侵袭性表达。 用小动物正电子发射计算机断层扫描确定αvβ6是否是一种有用的标志物 肿瘤转化的进展。在目标2中，我们将进行一项人类前瞻性队列研究 αvβ6成像。可疑PDAC和囊性胰腺病变(IPMN或MCN)的患者将获得标准的 CARE(SOC)治疗，抽吸物的分子分析和18F-αvPET 6-BP-β/CT。我们将比较a)SOC 和b)18F-αvβ6-BP-α/CT在危险分层中的分子检测 用切除的标本病理进行成像。在目标3中，我们将开发一种多路目标策略，以 在活体内同时询问两个分子标记。我们选择了αvβ6和Plectin-1作为初始 模型作为两个靶点已经在PDAC和基于多肽的靶向分子显像剂中被确定 每个目标都已存在。 这种有针对性的分子成像方法促进了个性化医学，使用αvβ6-Directed 影像识别高危先兆病变以进行介入，同时保留不必要的低风险病变 干预。组建的团队在分子探针开发和开发方面拥有丰富的专业知识和资源 胰腺癌检测联盟可以利用的小动物分子成像技术 未来分子成像探针的快速验证。

One of the major challenges of pancreatic ductal adenocarcinoma (PDAC) is the identification, development and validation of novel molecular markers and imaging probes that would enable earlier detection and provide a rational guide for treatment regimens. We are proposing the integrin subtype αvβ6 as a novel molecular imaging marker for further development and validation combined with a non-invasive peptide-based molecular imaging strategy for in vivo detection of disease progression. αvβ6 is an epithelial-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelial derived cancers. This receptor is often localized to the invasive front of tumors and plays a key role in invasion and metastasis. αvβ6 was initially identified in pancreatic cancer with the majority of human PDAC samples tested receiving the maximum score from IHC. The PI has developed an αvβ6-directed molecular imaging agent, 18F-αvβ6-binding-peptide (18F-αvβ6-BP), which has high affinity and selectivity for αvβ6 integrin and demonstrated favorable pharmacokinetics in tumor-bearing mice and non-human-primates. Approval to proceed with a first-in-human study was recently granted by the FDA. The overall goal of this U01 is to validate αvβ6 integrin as a non-invasive molecular imaging target for the early detection of PDAC with PET using 18F-αvβ6-BP. Our three Aims will run in parallel over this five year proposal. In Aim 1 a) we will evaluate αvβ6 expression in human pancreatic tissue (IPMN, MCN and PDAC), and b) we will evaluate αvβ6 expression non-invasively in murine pancreatic cancer progression models of IPMN or MCN to PDAC using small animal PET imaging to determine if αvβ6 is a useful marker to evaluate progression of neoplastic transformation. In Aim 2 we will perform a human prospective cohort study evaluating αvβ6 imaging. Patient with suspect PDAC and cystic pancreatic lesions (IPMN or MCN) will get standard of care (SOC) treatment, molecular analysis of the aspirate and 18F-αvβ6-BP-PET/CT. We will compare a) SOC and molecular testing with 18F-αvβ6-BP-PET/CT imaging in risk stratification and b) 18F-αvβ6-BP-PET/CT imaging with resected specimen pathology. In Aim 3 we will develop a multiplexed targeting strategy to interrogate two molecular markers simultaneously in vivo. We have selected αvβ6 and Plectin-1 as our initial model as both targets have been identified in PDAC and peptide-based targeted molecular imaging agents already exist for each target. This targeted molecular imaging approach facilitates personalized medicine, with αvβ6-directed imaging identifying high-risk precursor lesions for intervention while sparing low risk lesions unnecessary intervention. The team assembled has significant expertise and resources in molecular probe development and small-animal molecular imaging that can be leveraged by the Pancreatic Cancer Detection Consortium for rapid validation of future molecular imaging probes.