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Radiolabeled FAP inhibitors as new pantumoral radiopharmaceuticals for PET imaging: a pictorial essay

Abstract

Fibroblast activation protein (FAP)-targeted radiopharmaceuticals recently emerged as potential pantumoral agent for PET imaging. FAPi PET provides the opportunity to explore the tumor microenvironment, a highly heterogeneous and dynamic system of various non-malignant cells, by assessing the overexpression of FAP in cancer-associated fibroblasts. A significant increase in FAP expression can be found in several tumor subtypes, in which has been observed an increased tumor lesion uptake associated with low and favorable background, leading to a high detection rate of tumor location(s). This pictorial essay aims to present a selection of clinical cases highlighting the potential benefit of FAPi PET in different tumor subtypes, especially considering the higher diagnostic accuracy compared to FDG PET. We present clinical cases of breast cancer, lung cancer, gastric cancer, hepatocellular carcinoma, gynecological cancers and peritoneal carcinomatosis, as well as an introduction of the biodistribution of FAPi.

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References

  1. Jansen K, Heirbaut L, Cheng JD, Joossens J, Ryabtsova O, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, Van der Veken P (2013) Selective inhibitors of fibroblast activation protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold. ACS Med Chem Lett 4(5):491–496. https://doi.org/10.1021/ml300410d

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, Old LJ, Rettig WJ (1994) Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA 91(12):5657–5661. https://doi.org/10.1073/pnas.91.12.5657

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(Pt 23):5591–5596. https://doi.org/10.1242/jcs.116392

    CAS  Article  PubMed  Google Scholar 

  4. Dvorak HF (1986) Tumors wounds that do not heal similarities between tumor stroma generation and wound healing. New Engl J Med 315(26):1650–1659. https://doi.org/10.1056/NEJM198612253152606

    CAS  Article  PubMed  Google Scholar 

  5. Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, Jäger D, Mier W, Haberkorn U (2018) Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med 59:1415–1422. https://doi.org/10.2967/jnumed.118.210443

    CAS  Article  PubMed  Google Scholar 

  6. Giesel FL, Kratochwil C, Lindner T, Marschalek MM, Loktev A, Lehnert W, Debus J, Jäger D, Flechsig P, Altmann A, Mier W, Haberkorn U (2019) 68Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med 60(3):386–392. https://doi.org/10.2967/jnumed.118.215913

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, Adeberg S, Rathke H, Röhrich M, Winter H, Plinkert PK, Marme F, Lang M, Kauczor HU, Jäger D, Debus J, Haberkorn U, Giesel FL (2019) 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med 60(6):801–805. https://doi.org/10.2967/jnumed.119.227967

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Çermik TF, Ergül N, Yılmaz B, Mercanoğlu G (2022) Tumor imaging With 68Ga-DOTA-FAPI-04 PET/CT: comparison with 18F-FDG PET/CT in 22 different cancer types. Clin Nucl Med 47(4):e333–e339. https://doi.org/10.1097/RLU.0000000000004073

    Article  PubMed  Google Scholar 

  9. Mona CE, Benz MR, Hikmat F, Grogan TR, Lückerath K, Razmaria A, Riahi R, Slavik R, Girgis MD, Carlucci G, Kelly KA, French SW, Czernin J, Dawson DW, Calais J (2021) Correlation of 68Ga-FAPi-46 PET biodistribution with FAP expression by immunohistochemistry in patients with solid cancers: a prospective translational exploratory study. J Nucl Med. https://doi.org/10.2967/jnumed.121.262426

    Article  PubMed  Google Scholar 

  10. Hu K, Wang L, Wu H, Huang S, Tian Y, Wang Q, Xiao C, Han Y, Tang G (2021) [18F]FAPI-42 PET imaging in cancer patients: optimal acquisition time, biodistribution, and comparison with [68Ga]Ga-FAPI-04. Eur J Nucl Med Mol Imaging. https://doi.org/10.1007/s00259-021-05646-z

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16:582–598. https://doi.org/10.1038/nrc.2016.73

    CAS  Article  PubMed  Google Scholar 

  12. Kömek H, Can C, Güzel Y, Oruç Z, Gündoğan C, Yildirim ÖA, Kaplan İ, Erdur E, Yıldırım MS, Çakabay B (2021) 68Ga-FAPI-04 PET/CT, a new step in breast cancer imaging: a comparative pilot study with the 18F-FDG PET/CT. Ann Nucl Med 35:744–752. https://doi.org/10.1007/s12149-021-01616-5

    CAS  Article  PubMed  Google Scholar 

  13. Elboga U, Sahin E, Kus T, Cayirli YB, Aktas G, Uzun E, Cinkir HY, Teker F, Sever ON, Aytekin A, Yilmaz L, Aytekin A, Cimen U, Mumcu V, Kilbas B, Çelen YZ (2021) Superiority of 68Ga-FAPI PET/CT scan in detecting additional lesions compared to 18FDG PET/CT scan in breast cancer. Ann Nucl Med 35(12):1321–1331. https://doi.org/10.1007/s12149-021-01672-x

    CAS  Article  PubMed  Google Scholar 

  14. Farsad M (2020) FDG PET/CT in the staging of lung cancer. Curr Radiopharm 13(3):195–203. https://doi.org/10.2174/1874471013666191223153755

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Wang L, Tang G, Hu K, Liu X, Zhou W, Li H, Huang S, Han Y, Chen L, Zhong J, Wu H (2022) Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the evaluation of advanced lung cancer. Radiology 303(1):191–199. https://doi.org/10.1148/radiol.211424

    Article  PubMed  Google Scholar 

  16. Li Y, Lin X, Li Y, Lv J, Hou P, Liu S, Chen P, Wang M, Zhou C, Wang X (2022) Clinical utility of F-18 labeled fibroblast activation protein inhibitor (FAPI) for primary staging in lung adenocarcinoma: a prospective study. Mol Imaging Biol 24(2):309–320. https://doi.org/10.1007/s11307-021-01679-w

    CAS  Article  PubMed  Google Scholar 

  17. Wei Y, Cheng K, Fu Z, Zheng J, Mu Z, Zhao C, Liu X, Wang S, Yu J, Yuan S (2022) [18F]AlF-NOTA-FAPI-04 PET/CT uptake in metastatic lesions on PET/CT imaging might distinguish different pathological types of lung cancer. Eur J Nucl Med Mol Imaging 49(5):1671–1681. https://doi.org/10.1007/s00259-021-05638-z

    CAS  Article  PubMed  Google Scholar 

  18. Yun M (2014) Imaging of gastric cancer metabolism using 18 F-FDG PET/CT. J Gastric cancer 14(1):1–6. https://doi.org/10.5230/jgc.2014.14.1.1

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pang Y, Zhao L, Luo Z, Hao B, Wu H, Lin Q, Sun L, Chen H (2021) Comparison of 68Ga-FAPI and 18F-FDG Uptake in gastric, duodenal, and colorectal cancers. Radiology 298(2):393–402. https://doi.org/10.1148/radiol.2020203275

    Article  PubMed  Google Scholar 

  20. Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9(8):454–467. https://doi.org/10.1038/nrgastro.2012.115

    CAS  Article  PubMed  Google Scholar 

  21. Zhang Z, Jia G, Pan G, Cao K, Yang Q, Meng H, Yang J, Zhang L, Wang T, Cheng C, Zuo C (2022) Comparison of the diagnostic efficacy of 68 Ga-FAPI-04 PET/MR and 18F-FDG PET/CT in patients with pancreatic cancer. Eur J Nucl Med Mol Imaging. https://doi.org/10.1007/s00259-022-05729-5

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kauhanen SP, Komar G, Seppänen MP, Dean KI, Minn HR, Kajander SA, Rinta-Kiikka I, Alanen K, Borra RJ, Puolakkainen PA, Nuutila P, Ovaska JT (2009) A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer. Ann Surg 250(6):957–963. https://doi.org/10.1097/SLA.0b013e3181b2fafa

    Article  PubMed  Google Scholar 

  23. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, Heimbach JK (2018) Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases. Hepatology (Baltimore, MD) 68(2):723–750. https://doi.org/10.1002/hep.29913

    Article  Google Scholar 

  24. Oliva MR, Saini S (2004) Liver cancer imaging: role of CT, MRI US and PET. Cancer Imaging 4 Spec No A(Spec No A):S42–S46. https://doi.org/10.1102/1470-7330.2004.0011

    Article  PubMed  Google Scholar 

  25. Gallagher BM, Fowler JS, Gutterson NI, MacGregor RR, Wan CN, Wolf AP (1978) Metabolic trapping as a principle of oradiopharmaceutical design: some factors resposible for the biodistribution of [18F] 2-deoxy-2-fluoro-D-glucose. J Nucl Med 19(10):1154–1161

    CAS  PubMed  Google Scholar 

  26. Wang H, Zhu W, Ren S, Kong Y, Huang Q, Zhao J, Guan Y, Jia H, Chen J, Lu L, Xie F, Qin L (2021) 68Ga-FAPI-04 versus 18F-FDG PET/CT in the detection of hepatocellular carcinoma. Front Oncol 11:693640. https://doi.org/10.3389/fonc.2021.693640

    Article  PubMed  PubMed Central  Google Scholar 

  27. Carmona-Bozo JC, Manavaki R, Woitek R, Torheim T, Baxter GC, Caracò C, Provenzano E, Graves MJ, Fryer TD, Patterson AJ, Gilbert FJ (2021) Hypoxia and perfusion in breast cancer: simultaneous assessment using PET/MR imaging. Eur Radiol 31(1):333–344. https://doi.org/10.1007/s00330-020-07067-2

    Article  PubMed  Google Scholar 

  28. Siripongsatian D, Promteangtrong C, Kunawudhi A, Kiatkittikul P, Boonkawin N, Chinnanthachai C, Jantarato A, Chotipanich C (2022) Comparisons of quantitative parameters of Ga-68-labelled fibroblast activating protein inhibitor (FAPI) PET/CT and [18F]F-FDG PET/CT in patients with liver malignancies. Mol Imaging Biol. https://doi.org/10.1007/s11307-022-01732-2

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lakhani A, Khan SR, Bharwani N, Stewart V, Rockall AG, Khan S, Barwick TD (2017) FDG PET/CT pitfalls in gynecologic and genitourinary oncologic imaging. Radiographics 37(2):577–594. https://doi.org/10.1148/rg.2017160059

    Article  PubMed  Google Scholar 

  30. Dendl K, Koerber SA, Finck R, Mokoala KMG, Staudinger F, Schillings L, Heger U, Röhrich M, Kratochwil C, Sathekge M, Jäger D, Debus J, Haberkorn U, Giesel FL (2021) 68Ga-FAPI-PET/CT in patients with various gynecological malignancies. Eur J Nucl Med Mol Imaging 48(12):4089–4100. https://doi.org/10.1007/s00259-021-05378-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Coccolini F, Gheza F, Lotti M, Virzì S, Iusco D, Ghermandi C, Melotti R, Baiocchi G, Giulini SM, Ansaloni L, Catena F (2013) Peritoneal carcinomatosis. World J Gastroenterol 19(41):6979–6994. https://doi.org/10.3748/wjg.v19.i41.6979

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Zhao L, Pang Y, Luo Z, Fu K, Yang T, Zhao L, Sun L, Wu H, Lin Q, Chen H (2021) Role of [68Ga]Ga-DOTA-FAPI-04 PET/CT in the evaluation of peritoneal carcinomatosis and comparison with [18F]-FDG PET/CT. Eur J Nucl Med Mol Imaging 48(6):1944–1955. https://doi.org/10.1007/s00259-020-05146-6

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

Authors would thank the Nuclear Medicine Division of the Faculty of Medicine of the Yeditepe University, Turkey and the Division of Nuclear Medicine of the S. Orsola-Malpighi University Hospital IRCCS of Bologna, Italy for providing clinical cases. At Yeditepe University 68Ga-FAPi-04 synthesis was performed within the scope of the magistral drug production permit given by the Turkey Pharmaceuticals and Medical Devices Agency (E-24931227-000-535219). The evaluation of data was approved by the local ethics committee of the Yeditepe University (Decision no: 1576).

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Correspondence to Lighea Simona Airò Farulla.

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Airò Farulla, L.S., Demirci, E., Castellucci, P. et al. Radiolabeled FAP inhibitors as new pantumoral radiopharmaceuticals for PET imaging: a pictorial essay. Clin Transl Imaging (2022). https://doi.org/10.1007/s40336-022-00506-8

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  • DOI: https://doi.org/10.1007/s40336-022-00506-8

Keywords

  • PET
  • FAPi
  • Fibroblast activation protein
  • Cancer-associated fibroblast
  • Cancer imaging