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

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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.