A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection
Abstract Background Sarcomas represent a heterogeneous group of mesenchymal tumors that, despite accounting for only 1% of cancers worldwide, rank among the top five causes of cancer-related deaths in patients under 20 years old. Surgical resection remains the primary treatment for these malignancie...
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SpringerOpen
2025-07-01
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| Series: | EJNMMI Research |
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| Online Access: | https://doi.org/10.1186/s13550-025-01289-5 |
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| author | Feredun Azari Gregory T. Kennedy Ian Folkert Gregory Jones Ashley Chang Andrew Conner Elizabeth Bernstein Bilal Nadeem Neil T. Sullivan Evgeniy Eruslanov Steven Albelda Philip Low Sunil Singhal |
| author_facet | Feredun Azari Gregory T. Kennedy Ian Folkert Gregory Jones Ashley Chang Andrew Conner Elizabeth Bernstein Bilal Nadeem Neil T. Sullivan Evgeniy Eruslanov Steven Albelda Philip Low Sunil Singhal |
| author_sort | Feredun Azari |
| collection | DOAJ |
| description | Abstract Background Sarcomas represent a heterogeneous group of mesenchymal tumors that, despite accounting for only 1% of cancers worldwide, rank among the top five causes of cancer-related deaths in patients under 20 years old. Surgical resection remains the primary treatment for these malignancies, as effective systemic therapies are limited, particularly for high-grade disease. However, surgical outcomes are often compromised by incomplete resection, leading to high local and distal recurrence rates. Intraoperative molecular imaging has emerged as a promising approach to improve surgical outcomes but has been hindered by the lack of tumor-specific targeting agents. Fibroblast activation protein (FAP), selectively expressed by mesenchymal tumors and absent in healthy tissues, presents a promising target for fluorescence-guided cancer resections. Results We demonstrate that 41% of human sarcomas express FAP, with expression correlating with higher histologic grade. The FAP-S0456 optical tracer specifically bound to FAP-expressing sarcomas with minimal binding to normal tissues, exhibiting excellent tumor-to-background ratios (3.8 ± 0.43). In vitro studies confirmed FAP-S0456’s specificity for human FAP with a dissociation constant of approximately 10 nM. In murine xenograft models, the tracer accurately identified both primary tumors and pulmonary metastases of FAP-expressing sarcomas. Importantly, using needle confocal laser endomicroscopy, we demonstrated that FAP-S0456 enables real-time, single-cell visualization of metastatic tumor cells during surgery, including micrometastases not detected by conventional imaging. Conclusions FAP-S0456 represents a promising molecular imaging agent for the detection and surgical removal of primary and metastatic sarcomas. Its high specificity for FAP-expressing tumor cells, favorable biodistribution profile, and ability to detect microscopic disease offer potential to improve complete surgical resection. These findings support the development of FAP-targeted fluorescence-guided surgery for sarcoma patients, which may lead to improved oncologic outcomes, particularly for those with pulmonary metastases where complete surgical clearance is critical for survival. |
| format | Article |
| id | doaj-art-77982e83e12a4e56871482040b44f4bf |
| institution | Kabale University |
| issn | 2191-219X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj-art-77982e83e12a4e56871482040b44f4bf2025-08-20T04:02:44ZengSpringerOpenEJNMMI Research2191-219X2025-07-0115111810.1186/s13550-025-01289-5A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resectionFeredun Azari0Gregory T. Kennedy1Ian Folkert2Gregory Jones3Ashley Chang4Andrew Conner5Elizabeth Bernstein6Bilal Nadeem7Neil T. Sullivan8Evgeniy Eruslanov9Steven Albelda10Philip Low11Sunil Singhal12Department of Thoracic Surgery, University of PennsylvaniaDepartment of Thoracic Surgery, University of PennsylvaniaDepartment of Surgery, Hospital of the University of PennsylvaniaHeart, Vascular, and Thoracic Institute, Cleveland Clinic FoundationDepartment of Thoracic Surgery, University of PennsylvaniaHeart, Vascular, and Thoracic Institute, Cleveland Clinic FoundationPerelman School of Medicine, University of PennsylvaniaDepartment of Thoracic Surgery, University of PennsylvaniaDepartment of Thoracic Surgery, University of PennsylvaniaDepartment of Thoracic Surgery, University of PennsylvaniaDepartment of Pulmonary Medicine, Perelman School of MedicineDepartment of Chemistry, Purdue UniversityDepartment of Thoracic Surgery, University of PennsylvaniaAbstract Background Sarcomas represent a heterogeneous group of mesenchymal tumors that, despite accounting for only 1% of cancers worldwide, rank among the top five causes of cancer-related deaths in patients under 20 years old. Surgical resection remains the primary treatment for these malignancies, as effective systemic therapies are limited, particularly for high-grade disease. However, surgical outcomes are often compromised by incomplete resection, leading to high local and distal recurrence rates. Intraoperative molecular imaging has emerged as a promising approach to improve surgical outcomes but has been hindered by the lack of tumor-specific targeting agents. Fibroblast activation protein (FAP), selectively expressed by mesenchymal tumors and absent in healthy tissues, presents a promising target for fluorescence-guided cancer resections. Results We demonstrate that 41% of human sarcomas express FAP, with expression correlating with higher histologic grade. The FAP-S0456 optical tracer specifically bound to FAP-expressing sarcomas with minimal binding to normal tissues, exhibiting excellent tumor-to-background ratios (3.8 ± 0.43). In vitro studies confirmed FAP-S0456’s specificity for human FAP with a dissociation constant of approximately 10 nM. In murine xenograft models, the tracer accurately identified both primary tumors and pulmonary metastases of FAP-expressing sarcomas. Importantly, using needle confocal laser endomicroscopy, we demonstrated that FAP-S0456 enables real-time, single-cell visualization of metastatic tumor cells during surgery, including micrometastases not detected by conventional imaging. Conclusions FAP-S0456 represents a promising molecular imaging agent for the detection and surgical removal of primary and metastatic sarcomas. Its high specificity for FAP-expressing tumor cells, favorable biodistribution profile, and ability to detect microscopic disease offer potential to improve complete surgical resection. These findings support the development of FAP-targeted fluorescence-guided surgery for sarcoma patients, which may lead to improved oncologic outcomes, particularly for those with pulmonary metastases where complete surgical clearance is critical for survival.https://doi.org/10.1186/s13550-025-01289-5Fibroblast activation proteinTargeted optical tracer identifiesFAP expressing primaryMicro metastatic tumors |
| spellingShingle | Feredun Azari Gregory T. Kennedy Ian Folkert Gregory Jones Ashley Chang Andrew Conner Elizabeth Bernstein Bilal Nadeem Neil T. Sullivan Evgeniy Eruslanov Steven Albelda Philip Low Sunil Singhal A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection EJNMMI Research Fibroblast activation protein Targeted optical tracer identifies FAP expressing primary Micro metastatic tumors |
| title | A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| title_full | A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| title_fullStr | A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| title_full_unstemmed | A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| title_short | A fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| title_sort | fibroblast activation protein targeted optical tracer for identifying primary and metastatic sarcoma during resection |
| topic | Fibroblast activation protein Targeted optical tracer identifies FAP expressing primary Micro metastatic tumors |
| url | https://doi.org/10.1186/s13550-025-01289-5 |
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