Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment

Siveke, Jens T.

doi:10.2967/jnumed.118.214361

Cited by 54 publications

(39 citation statements)

References 18 publications

(16 reference statements)

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“…Expression of FAP was described in association to diverse carcinomas, such as in breast and colorectal carcinomas, and in oropharyngeal cancer [11,14,15]. In its active dimeric form, FAP acts as an exo-and endopeptidase, influencing the proliferation, migration, and invasion of tumor cells [15][16][17][18]. In contrast, FAP is absent in normal adult tissues [19].…”

Section: Introductionmentioning

confidence: 99%

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

Serfling

Zhi

Schirbel

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [18F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [18F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer’s tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer’s tonsillar ring, the novel PET tracer [68Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. Methods Eight patients with suspicion of a malignant tumor in Waldeyer’s tonsillar ring or a CUP syndrome were examined. PET/CT scans with [18F]-FDG and [68Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. Results Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [18F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [68Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for 18F-FDG and 16.06 ± 6.29 for 68Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [18F]FDG and 3.55 ± 0.47 for [68Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [18F] FDG (p = 0.03). Mean TBRmax for the [68Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [18F]FDG (10.90 vs. 4.11). Conclusion Non-invasive imaging of FAP expression by [68Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [18F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [68Ga]FAPI PET/CT imaging.

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Section: Introductionmentioning

confidence: 99%

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

Serfling

Zhi

Schirbel

et al. 2020

Eur J Nucl Med Mol Imaging

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“…Sever al tumor entities, such as breast, colon, and pancreatic carcinomas, are characterized by a strong desmoplastic reaction (1). Cancer-associated fibroblasts and extracellular fibrosis can contribute up to 90% of the gross tumor mass, leaving original tumor cells in the minority (2,3).…”

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confidence: 99%

⁶⁸Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

et al. 2019

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The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on 68 Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. Methods: 68 Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by 18 F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122-312 MBq of 68 Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUV max and SUV mean (60% isocontour). Results: Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUV max (.12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest 68 Ga-FAPI uptake (average SUV max , 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUV max of hepatocellular, colorectal, head-neck, ovarian, pancreatic, and prostate cancer was intermediate . SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUV max , 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6fold in the high-intensity uptake group. Conclusion: Several highly prevalent cancers presented with remarkably high uptake and image contrast on 68 Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy. ://jnm.snmjournals.org/content/60/6/801 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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“…(Kalluri 2016.). FAP is able to operate the tumor cell behavior, therefore it can be used as an imaging tracer for many cancer types particularly colorectal, ovarian, pancreatic, and hepatocellular carcinomas which are identified by a strong desmoplastic reaction (Gascard and Tlsty 2017;Siveke 2018). Recently, fibroblast activation protein-specific inhibitor (FAPI) decorated radiopharmaceuticals have been great of interest for the diagnosis of various tumor species (Fig.…”

Section: Introductionmentioning

confidence: 99%

Fully-automated synthesis of 177Lu labelled FAPI derivatives on the module modular lab-Eazy

Eryilmaz¹,

Kılbaş²

2021

EJNMMI radiopharm. chem.

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Background To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively presented. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield ([177Lu]Lu-FAPI-04; 88% ± 3, [177Lu]Lu-FAPI-46; 86% ± 3). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals was accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template. Graphical abstract

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Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment

Cited by 54 publications

References 18 publications

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

⁶⁸Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

Fully-automated synthesis of 177Lu labelled FAPI derivatives on the module modular lab-Eazy

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Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment

Cited by 54 publications

References 18 publications

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

Improved cancer detection in Waldeyer’s tonsillar ring by 68Ga-FAPI PET/CT imaging

68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer

Fully-automated synthesis of 177Lu labelled FAPI derivatives on the module modular lab-Eazy

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⁶⁸Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer