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

胰腺导管腺癌 (PDA) 中癌症相关成纤维细胞 (CAF) 的体内 68Ga-成纤维细胞激活蛋白抑制剂 (FAPI)-46 PET 定量成像

基本信息

  • 批准号:
    10685439
  • 负责人:
  • 金额:
    $ 59.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

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.
项目总结 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年将成为第二大事业。其特有的促结缔组织间质,构成 占其体积的60%-70%,是导致惨淡结局的关键因素之一。成纤维细胞活化 表达蛋白质(FAP)的肿瘤相关成纤维细胞(CAF)是最重要的间质细胞之一 因为它们在癌症的发生、纤维化、肿瘤的生长、转移、 和治疗耐药。PDA中FAP的表达是预后不良的独立预测因子。缺乏 非侵入性工具在体内准确描述CAF在时间和空间上的身份和功能是至关重要的 翻译现有的肿瘤微环境知识以解决未得到满足的临床需求的障碍。 68Ga-FAP-Inhibitor(FAPI)-46已成为一种具有最佳性能的PET放射性示踪剂,用于FAP靶向临床 PDA中的影像和治疗声学。这些包括对FAP的低纳米分子亲和力,近乎完全的内化 与FAP结合的放射性,缺乏生理性摄取,血液快速清除和肿瘤滞留时间延长, 和操作特性,提供了极大的灵活性以适应临床环境、PET扫描仪配置文件、 以及PDA患者的工作流程。传统上,漫长的监管和报销审批路径相结合 由于比较研究的高昂成本,推迟了临床获得有前途的精密工具,如68Ga- FAPI-46 PET。因此,对于治疗用放射性示踪剂如68Ga-FAPI-46的临床翻译,一位学者- 基于优势互补和连贯的临床开发战略的产业伙伴关系(AIP)是 需要降低风险并提高达到FDA标准和消费者期望的可能性。我们的 AIP-Mayo诊所和Sofie Biosciences(“Sofie”)-将按照以下规定进行临床调查 FDA标准形成新药申请(NDA)的基础,目标是提供新的能力 用户,与本FOA的意图一致。我们的假设是68Ga-FAPI-46PET将是一项准确的技术 为了检测和量化CAF和从68Ga-FAPI-46衍生的指标,PET将成为PDA的新生物标志物。 在目标1中,以免疫表型为参考标准,68Ga-FAPI-46的敏感性和特异性 将评估PET在PDA中CAF的检测和量化,以及读者间和内部 阅读器的可靠性以及68Ga-FAPI-46PET生物标志物对新佐剂的响应动态变化 治疗。在目标2中,68Ga-FAPI-46 PET将被比较、关联并与其他 不同的研究以改善手术前分期和预测手术后结果。我们的AIP有 有可能提供一种非侵入性的分子成像分析,可以更好地洞察疾病生物学, 影响临床实践,预测结果,加强现有的治疗方法,并产生一条新的途径 治疗方法。鉴于FAPI成像和治疗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扩展到其他肿瘤学和非肿瘤学应用。

项目成果

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Ajit Harishkumar Goenka其他文献

MR-guided abdominal biopsy using a 1.5-Tesla closed system: a feasibility study
  • DOI:
    10.1007/s00261-009-9504-0
  • 发表时间:
    2009-03-04
  • 期刊:
  • 影响因子:
    2.200
  • 作者:
    Chandan Jyoti Das;Ajit Harishkumar Goenka;Deep Narayan Srivastava
  • 通讯作者:
    Deep Narayan Srivastava

Ajit Harishkumar Goenka的其他文献

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