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

胰腺导管腺癌（PDAC）的主要挑战之一是识别， 开发和验证新的分子标记物和成像探针，使早期检测成为可能 为治疗方案提供合理指导。我们提出整合素亚型αvβ6作为一种新的 用于进一步开发和验证的分子成像标记物与非侵入性的基于肽的 用于体内检测疾病进展的分子成像策略。αvβ6是上皮特异性细胞 在健康成人上皮中检测不到但在宽范围内显著上调的表面受体 上皮来源的癌症。这种受体通常定位于肿瘤的侵袭性前沿， 在侵袭和转移方面。αvβ6最初在胰腺癌中被发现， 检测的PDAC样本获得IHC的最大评分。PI开发了一个αvβ6定向 18 F-αv β 6-BP是一种对αvβ6具有高度亲和性和选择性的分子显像剂 整合素，并在荷瘤小鼠和非人灵长类动物中表现出有利的药代动力学。 FDA最近批准进行首次人体研究。 本U 01的总体目标是验证αvβ6整合素作为非侵入性分子成像靶点， 应用18 F-αvβ6-BP进行PET显像早期发现PDAC。我们的三个目标将在这五年内并行不悖 提议在目的1a）中，我们将评估αvβ6在人胰腺组织（IPMN、MCN和PDAC）中的表达， 和B）我们将在以下小鼠胰腺癌进展模型中非侵入性地评估αvβ6表达： 使用小动物PET成像确定αvβ6是否是评估PDAC的有用标志物 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显像。疑似PDAC和囊性胰腺病变（IPMN或MCN）的患者将接受标准的 护理（SOC）治疗、抽吸物的分子分析和18 F-αvβ6-BP-PET/CT。我们将比较a）SOC 在风险分层中使用18 F-αvβ6-BP-PET/CT成像进行分子检测，以及B）18 F-αvβ6-BP-PET/CT 与切除标本病理学成像。在目标3中，我们将开发一种多重靶向策略， 在体内同时询问两种分子标记物。我们选择αvβ6和Plectin-1作为我们的初始 作为两种靶点的模型已经在PDAC和基于肽的靶向分子成像剂中被确定 每个目标都存在。 这种靶向分子成像方法有助于个性化医疗， 成像识别高风险前驱病变进行干预，同时保留不必要的低风险病变 干预该团队在分子探针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小动物分子成像， 快速验证未来的分子成像探针。

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.