Search

Purpose: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 , a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC)., Methods: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18 F-FDG, [ 18 F]AlF-NOTA-FAPI-04, and [ 68 Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen., Results: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18 F-FDG and [ 18 F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12., Conclusion: The combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs., (© 2024. The Author(s).)

Purpose: The upregulation of fibroblast activation protein (FAP) expression has been observed in various cancers, including metastatic breast carcinoma, prompting research into small molecule inhibitors for both diagnostic and therapeutic purposes. While the diagnostic value of PET/CT imaging using 68  Ga- or 18 F-labelled FAPi-monomers in breast cancer diagnosis is well-established, there is a significant need for therapeutic analogs. This retrospective study aimed to assess the safety and effectiveness of [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage breast cancer who had previously undergone [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans to confirm the expression of FAP., Materials and Methods: Between November 2020 and March 2023, a compassionate treatment approach was utilized to administer [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy to heavily pretreated patients with advanced breast cancer. Nineteen patients (18 females, 1 male) with metastatic breast cancer participated in the study, with an average age of 44.6 ± 10.7 years. The therapy was administered at intervals of 8 to 12 weeks, and the median follow-up duration was 14 months. The primary objective of the study was to assess molecular response using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans, with response evaluation based on the PERCIST criteria. Secondary endpoints included overall survival (OS), progression-free survival (PFS), clinical response assessment, and safety evaluation using CTCAE v5.0 guidelines., Results: A total of 65 cycles were administered, with a mean cumulative activity of 19 ± 5.7 GBq (510 ± 154 mCi) ranging from 11 to 33.3 GBq (300 to 900 mCi) of [ 177 Lu]Lu-DOTAGA.FAPi dimer. The number of cycles ranged from 2 to 6, with a median of 3 cycles. The treatment protocol consisted of different numbers of cycles administered to the patients: specifically, two cycles were given to five patients, three cycles to nine patients, four cycles to one patient, and six cycles to four patients. Most patients had invasive/infiltrative ductal carcinoma (94.7%), while a small percentage had invasive lobular carcinoma (5.3%). All patients had bone metastases, and five of them also had liver involvement, while seven had brain metastases. Response assessment using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans showed that 25% of the 16 patients evaluated had partial remission, while 37.5% exhibited disease progression. According to the VAS response criteria, 26.3% achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. The clinical disease control rate was promising, with 95% of patients achieving disease control. The clinical objective response rate was 84%. The median follow-up period was 14 months. At the time of analysis, the median overall survival was 12 months, and the median progression-free survival was 8.5 months. Notably, no severe hematological, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study., Conclusion: The findings suggest that [ 177 Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [ 177 Lu]Lu-DOTAGA.FAPi dimer treatment demonstrated promising efficacy in patients with advanced breast cancer, as indicated by high disease control rates, favorable response outcomes, and acceptable safety profile. Further research and longer follow-up are warranted to assess long-term outcomes and validate these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [ 18 F]F-FDG PET/CT serves as a widely used and valuable diagnostic imaging method. However, there is growing interest in utilizing molecular imaging probes that target cancer-associated fibroblasts (CAFs) as an alternative approach. This study sought to compare the diagnostic capabilities of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT in patients with RAI-R-FCTC., Methods: In this retrospective study, a total of 117 patients with RAI-R-FCTC were included. The study population consisted of 68 females and 49 males, with a mean age of 53.2 ± 11.7 years. The aim of the study was to perform a comprehensive qualitative and quantitative assessment of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT scans in RAI-R-FCTC patients. The qualitative assessment involved comparing patient-based and lesion-based visual interpretations of both scans, while the quantitative assessment included analyzing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings obtained from the scans were validated by correlating them with morphological findings from diagnostic computed tomography and/or histopathological examination., Results: Among the 117 RAI-R-FCTC patients, 60 had unilateral local disease, and 9 had bilateral lesions with complete concordance in the detection rate on both PET scans. [ 68 Ga]Ga-DOTA.SA.FAPi had a higher detection rate for lymph nodes (95.4% vs 86.6%, p<0.0001), liver metastases (100% vs. 81.3%, p<0.0001), and brain metastases (100% vs. 39%, p<0.0001) compared to [ 18 F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [ 68 Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [ 18 F]F-FDG had a detection rate of 64.6%. Remarkably, [ 68 Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [ 18 F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [ 68 Ga]Ga-DOTA.SA.FAPi exhibited higher uptake., Conclusion: The study results demonstrate the superior performance of [ 68 Ga]Ga-DOTA.SA.FAPi compared to [ 18 F]F-FDG PET/CT in detecting lymph nodal, liver, bowel, and brain metastases in patients with RAI-R-FCTC. These findings highlight the potential of [ 68 Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [ 18 F]F-FDG PET/CT in the imaging of RAI-R-FCTC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The present study aims at evaluating the preclinical and the clinical performance of [ 68 Ga]Ga-DATA 5m. SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature., Methods: [ 68 Ga]Ga-DATA 5m .SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [ 68 Ga]Ga-DATA 5m .SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake., Results: [ 68 Ga]Ga-DATA 5m .SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [ 68 Ga]Ga-DATA 5m .SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high., Conclusion: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [ 68 Ga]Ga-DATA 5m .SA.FAPi as a diagnostic tool for FAP imaging., (© 2023. The Author(s).)

Purpose: [ 68 Ga]Ga-labeled fibroblast activation protein inhibitors ([ 68 Ga]Ga-FAPi) have shown promising preclinical and clinical results in PET imaging. The present study aimed to evaluate the biodistribution, pharmacokinetics, and dosimetry of [ 68 Ga]Ga-DOTA.SA.FAPi, another modified FAPi tracer, and performed a head-to-head comparison with [ 18 F]F-FDG PET/CT scans in patients with various cancers., Methods: In this prospective study, patients underwent both [ 18 F]F-FDG and [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT scans 60 min post-injection (p.i.). Dosimetry studies were conducted in three patients using [ 68 Ga]Ga-DOTA.SA.FAPi serial time-point imaging. The absorbed dose was calculated using OLINDA/EXM 2.2 software. Quantification of the uptake of the tracers was assessed using standardized uptake values corrected for lean body mass (SUL)., Results: Fifty-four patients (mean age; 48.4 years) with 14 types of cancers involving 37% breast, 24% lung, 7.4% head and neck (H&N), and remaining 31.6% patients with other histologies were evaluated prospectively. Physiological uptake of [ 68 Ga]Ga-DOTA.SA.FAPi was observed in the liver, kidneys, pancreas, heart contents, and to a lesser extent in the lacrimals, oral mucosa, salivary glands, and thyroid glands. Uptake in the target lesions on [ 68 Ga]Ga-DOTA.SA.FAPi scan was initiated at 10 min, and no additional lesions were detected in the delayed acquisition time points. The pancreas was the organ with the highest absorbed dose (5.46E-02 mSv/MBq). While the patient-based comparison between the radiotracers revealed complete concordance in the detection of primary, pleural thickening, bone and liver metastases, and second primary malignancy, discordant findings were observed in the detection of lymph node (7.5%), lung nodules (5.6%), and brain metastases (2%). According to the site of primary disease, patients with H&N cancers demonstrated the highest SULpeak and average (avg) values on [ 68 Ga]Ga-DOTA.SA-FAPi which was similar to the values of [ 18 F]F-FDG [(SULpeak: 15.4 vs. 14.2; P-0.680) (SULavg: 8.3 vs. 7.9; P-0.783)]. The lowest uptake was observed in lung cancers with both the radiotracers [(SULpeak: 5.8 vs. 7.4; P-0.238) (SULavg: 4.9 vs. 5.3; P-0.313)]. A significantly higher SULpeak and SULavg for brain metastases to normal brain parenchyma ratios were observed on [ 68 Ga]Ga-DOTA.SA.FAPi in contrast to the [ 18 F]F-FDG values {SULpeak: median: 59.3 (IQR: 33.5-130.8) versus 1.5 (1-2.3); P-0.028}. Except for brain metastases, comparable SULpeak and average values were noted between the radiotracers in all other regions of metastases with no significant difference., Conclusion: [ 68 Ga]Ga-DOTA.SA.FAPi is a promising alternative among the FAPI class of molecules and performed well as compared to standard-of-care radiotracer [ 18 F]F-FDG in the diagnosis of various cancers.