In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation
Abstract Background Fibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in se...
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SpringerOpen
2024-12-01
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| Online Access: | https://doi.org/10.1186/s13550-024-01191-6 |
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| author | Circe D. van der Heide Joana D. Campeiro Eline A. M. Ruigrok Lilian van den Brink Shashikanth Ponnala Shawn M. Hillier Simone U. Dalm |
| author_facet | Circe D. van der Heide Joana D. Campeiro Eline A. M. Ruigrok Lilian van den Brink Shashikanth Ponnala Shawn M. Hillier Simone U. Dalm |
| author_sort | Circe D. van der Heide |
| collection | DOAJ |
| description | Abstract Background Fibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in selecting promising FAP-targeted radiopharmaceuticals and for obtaining an increased understanding of factors essential for FAP-TRT improvement. FAP is mainly expressed by cancer-associated fibroblasts in the tumor stroma and less on cancer cells themselves. Therefore, other (complex) factors impact FAP-TRT efficacy compared to currently clinically applied TRT strategies. For accurate evaluation of these aspects, selection of a representative preclinical model is important. Currently mainly human cancer cell lines transduced to (over)express FAP are applied, lacking clinical representation. It is unclear how these and more physiological FAP-expressing models compare to each other, and whether/how the model influences the study outcome. We aimed to address this by comparing FAP tracer behavior in FAP-transduced HT1080-huFAP and HEK293-huFAP cells, and endogenous FAP-expressing U-87 MG cancer cells and PS-1 pancreatic stellate cells. [111In]In-FAPI-46 and a fluorescent FAP-targeted tracer (RTX-1370S) were used to compare tracer binding/uptake and localization in vitro and ex vivo. Additionally, FAP expression was determined with RT-qPCR and anti-FAP IHC. Results Although FAP expression was highest in HEK293-huFAP cells and cell line derived xenografts, this did not result in the highest tracer uptake. [111In]In-FAPI-46 uptake was highest in HT1080-huFAP, closely followed by HEK293-huFAP, and a 6-10-fold lower uptake for U-87 MG and PS-1 cells. However, ex vivo U-87 MG xenografts only showed a 2-fold lower binding compared to HT1080-huFAP and HEK293-huFAP xenografts, mainly because the cell line attracts murine fibroblasts as demonstrated in our RT-qPCR and IHC studies. Conclusions The interaction between FAP and FAP-targeted tracers differs between models, indicating the need for appropriate model selection and that comparing results across studies using different models is difficult. |
| format | Article |
| id | doaj-art-3c9a4964d6cd44f694ffdf3cbf59bb8e |
| institution | DOAJ |
| issn | 2191-219X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | SpringerOpen |
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| series | EJNMMI Research |
| spelling | doaj-art-3c9a4964d6cd44f694ffdf3cbf59bb8e2025-08-20T02:43:26ZengSpringerOpenEJNMMI Research2191-219X2024-12-0114111310.1186/s13550-024-01191-6In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluationCirce D. van der Heide0Joana D. Campeiro1Eline A. M. Ruigrok2Lilian van den Brink3Shashikanth Ponnala4Shawn M. Hillier5Simone U. Dalm6Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Centre RotterdamDepartment of Radiology & Nuclear Medicine, Erasmus MC University Medical Centre RotterdamDepartment of Radiology & Nuclear Medicine, Erasmus MC University Medical Centre RotterdamDepartment of Radiology & Nuclear Medicine, Erasmus MC University Medical Centre RotterdamRatio Therapeutics, Inc.Ratio Therapeutics, Inc.Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Centre RotterdamAbstract Background Fibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in selecting promising FAP-targeted radiopharmaceuticals and for obtaining an increased understanding of factors essential for FAP-TRT improvement. FAP is mainly expressed by cancer-associated fibroblasts in the tumor stroma and less on cancer cells themselves. Therefore, other (complex) factors impact FAP-TRT efficacy compared to currently clinically applied TRT strategies. For accurate evaluation of these aspects, selection of a representative preclinical model is important. Currently mainly human cancer cell lines transduced to (over)express FAP are applied, lacking clinical representation. It is unclear how these and more physiological FAP-expressing models compare to each other, and whether/how the model influences the study outcome. We aimed to address this by comparing FAP tracer behavior in FAP-transduced HT1080-huFAP and HEK293-huFAP cells, and endogenous FAP-expressing U-87 MG cancer cells and PS-1 pancreatic stellate cells. [111In]In-FAPI-46 and a fluorescent FAP-targeted tracer (RTX-1370S) were used to compare tracer binding/uptake and localization in vitro and ex vivo. Additionally, FAP expression was determined with RT-qPCR and anti-FAP IHC. Results Although FAP expression was highest in HEK293-huFAP cells and cell line derived xenografts, this did not result in the highest tracer uptake. [111In]In-FAPI-46 uptake was highest in HT1080-huFAP, closely followed by HEK293-huFAP, and a 6-10-fold lower uptake for U-87 MG and PS-1 cells. However, ex vivo U-87 MG xenografts only showed a 2-fold lower binding compared to HT1080-huFAP and HEK293-huFAP xenografts, mainly because the cell line attracts murine fibroblasts as demonstrated in our RT-qPCR and IHC studies. Conclusions The interaction between FAP and FAP-targeted tracers differs between models, indicating the need for appropriate model selection and that comparing results across studies using different models is difficult.https://doi.org/10.1186/s13550-024-01191-6Cancer-associated fibroblast (CAF)Fibroblast activation protein (FAP)Targeted radionuclide therapy (TRT)Radionuclide theranosticsPreclinical models |
| spellingShingle | Circe D. van der Heide Joana D. Campeiro Eline A. M. Ruigrok Lilian van den Brink Shashikanth Ponnala Shawn M. Hillier Simone U. Dalm In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation EJNMMI Research Cancer-associated fibroblast (CAF) Fibroblast activation protein (FAP) Targeted radionuclide therapy (TRT) Radionuclide theranostics Preclinical models |
| title | In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation |
| title_full | In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation |
| title_fullStr | In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation |
| title_full_unstemmed | In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation |
| title_short | In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation |
| title_sort | in vitro and ex vivo evaluation of preclinical models for fap targeted theranostics differences and relevance for radiotracer evaluation |
| topic | Cancer-associated fibroblast (CAF) Fibroblast activation protein (FAP) Targeted radionuclide therapy (TRT) Radionuclide theranostics Preclinical models |
| url | https://doi.org/10.1186/s13550-024-01191-6 |
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