Quantitative In Vivo 68Ga-Fibroblast-Activation-Protein-Inhibitors (FAPI)-46 PET Imaging of Cancer-Associated Fibroblasts (CAFs) in Pancreatic Ductal Adenocarcinoma (PDA)

项目摘要 胰腺导管腺癌（PDA）是美国癌症相关死亡的第三大原因， 预计到2030年将成为第二大原因。其特征性的促结缔组织增生基质， 其体积的60-70%，是导致惨淡结果的关键因素之一。成纤维细胞活化 表达FAP蛋白的癌相关成纤维细胞（CAFs）是肿瘤细胞中最重要的基质细胞之一， 因为它们在癌发生、纤维化、肿瘤生长、转移、 和治疗抗性。FAP在PDA中的表达是不良预后的独立预测因子。缺乏 非侵入性工具，以精确地描绘CAF身份和功能的时间和空间在体内是一个关键 肿瘤微环境的现有知识的翻译障碍，以解决未满足的临床需求。 68 Ga-FAP-抑制剂（FAPI）-46已经成为PET放射性示踪剂，其具有用于FAP靶向临床治疗的最佳性质。 影像学和治疗诊断学。这些包括对FAP的低纳摩尔亲和力，FAP的几乎完全内化，以及FAP的几乎完全内化。 与FAP结合的放射性，不存在生理摄取，快速血液清除和延长肿瘤滞留， 和操作特性，提供了巨大的灵活性，以适应临床环境，PET扫描仪配置文件， 和工作流程。传统上，漫长的监管和报销审批途径相结合 由于比较研究的成本高昂，推迟了临床使用有前途的精密工具，例如68 Ga- FAPI-46 PET。因此，对于治疗诊断放射性示踪剂如68 Ga-FAPI-46的临床转化，学术界认为， 基于互补优势和一致的临床开发战略的工业伙伴关系（AIP）， 需要降低风险并提高满足FDA标准和消费者期望的可能性。我们 AIP -马约诊所和Sofie Biosciences（“SOFIE”）-将按照以下要求开展临床研究： FDA标准构成新药申请（NDA）的基础，目标是提供一种新的能力， 用户，符合本FOA的意图。我们的假设是，68 Ga-FAPI-46 PET将是一种准确的技术， 以检测和定量CAF，并且来自68 Ga-FAPI-46 PET的度量将是PDA中的新生物标志物。 目的1：以免疫表型为参考标准，对68 Ga-FAPI-46的敏感性和特异性进行了研究。 将评价PET以检测和定量PDA中的CAF，沿着阅片员间和阅片员内 读片者的可靠性，以及68 Ga-FAPI-46 PET生物标志物对新辅助化疗反应的动态变化 治疗在目标2中，68 Ga-FAPI-46 PET将与其他机制进行比较、关联和组合。 不同的调查，以改善术前分期和预测手术后的结果。我们的AIP拥有 提供非侵入性分子成像分析的潜力，可以提供对疾病生物学的更深入了解， 影响临床实践，预测结果，增强现有疗法，并产生一种新途径 治疗方法。鉴于FAPI成像和治疗诊断学的广泛和不断发展的作用，我们的AIP具有 有可能将我们的影响从PDA扩展到其他肿瘤和非肿瘤应用。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the USA and is anticipated to become the second leading cause by 2030. Its characteristic desmoplastic stroma, constituting 60–70% of its volume, is one of the critical factors that contributes to the dismal outcomes. Fibroblast activation protein (FAP)-expressing Cancer-Associated Fibroblasts (CAFs) are one of the most important stromal constituents because they play a fundamental role in the carcinogenesis, fibrosis, tumor growth, metastases, and treatment resistance. FAP expression in PDA is an independent predictor of poor outcomes. Lack of noninvasive tools to precisely profile CAF identity and function both temporally and spatially in vivo is a critical barrier for translation of existing knowledge of the tumor microenvironment to address unmet clinical needs. 68Ga-FAP-inhibitor (FAPI)-46 has emerged as a PET radiotracer with optimal properties for FAP-targeted clinical imaging and theranostics in PDA. These include low nanomolar affinity to FAP, near-complete internalization of radioactivity bound to FAP, absence of physiologic uptake, rapid blood clearance and prolonged tumor retention, and operational characteristics that offer tremendous flexibility to suit the clinical context, PET scanner profile, and workflow for patients with PDA. Traditionally, long regulatory and reimbursement approval pathways coupled with high costs of comparative studies have delayed clinical access to promising precision tools such as 68Ga- FAPI-46 PET. Thus, for the clinical translation of a theranostic radiotracer such as 68Ga-FAPI-46, an academic- industrial partnership (AIP) based on complementary strengths and a coherent clinical development strategy is needed to reduce the risk and raise the likelihood of meeting FDA standards and consumer expectations. Our AIP - Mayo Clinic and Sofie Biosciences (“SOFIE”) - will undertake a clinical investigation in compliance with FDA standards to form the basis of a new drug application (NDA) with the goal to deliver a new capability to end users, consistent with this FOA’s intent. Our hypothesis is that 68Ga-FAPI-46 PET will be an accurate technique to detect and quantify CAFs and that metrics derived from 68Ga-FAPI-46 PET will be novel biomarkers in PDA. In Aim 1, using immunophenotyping as the reference standard, the sensitivity and specificity of 68Ga-FAPI-46 PET will be evaluated for the detection and quantification of CAFs in PDA, along with inter-reader and intra- reader reliability, and the dynamic changes in 68Ga-FAPI-46 PET biomarkers in response to neoadjuvant treatment. In Aim 2, 68Ga-FAPI-46 PET will be compared, correlated, and combined with other mechanistically distinct investigations to improve pre-surgical staging and to predict post-surgical outcomes. Our AIP has the potential to deliver a noninvasive molecular imaging assay that can provide greater insight into disease biology, impact clinical practice, predict outcomes, potentiate existing therapeutics, and yield a pathway to novel therapeutic approaches. Given the wide and evolving role of FAPI imaging and theranostics, our AIP has the potential to scale our impact beyond PDA to other oncologic and non-oncologic applications.