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European Journal of Nuclear Medicine... Sep 2022Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor...
PURPOSE
Fibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies.
METHODS
FAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule-based FAP-targeting agent.
RESULTS
Immunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of Ga-FAP-2286, In-FAP-2286, and Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46.
CONCLUSION
In preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of Ga-FAP-2286 for imaging and Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.
Topics: Adult; Animals; Cell Line, Tumor; Fibroblasts; Gallium Radioisotopes; HEK293 Cells; Humans; Mice; Radionuclide Imaging; Sarcoma; Tissue Distribution; Tumor Microenvironment
PubMed: 35608703
DOI: 10.1007/s00259-022-05842-5 -
The British Journal of Radiology Feb 2023Fibroblast-activation protein (FAP) is a serine protease classified in the dipeptidyl peptidase 4 (DPP4) family. FAP is predominantly expressed in activated fibroblasts... (Review)
Review
Fibroblast-activation protein (FAP) is a serine protease classified in the dipeptidyl peptidase 4 (DPP4) family. FAP is predominantly expressed in activated fibroblasts such as the cancer-associated fibroblasts (CAFs). FAP expression in CAFs is associated with tumor progression and poor prognosis in solid cancers. Recently, radiolabeled FAP inhibitors (FAPI) has been developed, which enables positron emission tomography (PET) imaging of FAP. FAPI PET/CT can provide a higher tumor-to-background ratio (TBR) than F-fludeoxyglucose PET/CT in various cancers, and thus has attracted substantial attention. As studies on FAPI PET grow in number and size, incidental findings related to non-oncologic conditions have been increasingly reported. FAPI PET uptake has been reported in various conditions such as benign tumors, fibrotic, granulomatosis, scarring/wound, degenerative diseases, and inflammatory diseases.The knowledge of physiological and non-oncologic causes of FAPI uptake is indispensable for accurate FAPI PET/CT interpretation and can help appropriate management of incidental findings on FAPI PET/CT in patients referred for cancer staging indications. In this review article, we describe for each organ system (Brain, Oral mucosa, Salivary Glands, Thyroid, Lung, Myocardium, Breast, Esophagus, Stomach, Intestine, Liver, Gallbladder, Pancreas, Spleen, Kidney, , Uterus, Bone marrow, Joints, Muscle, Vessels, Lymph nodes), the patterns of physiological FAPI uptake and the main causes of non-oncological uptake reported from the literature with FAPI-02, FAPI-04 and FAPI-46. We also illustrate some examples from our institutional database at UCLA.
Topics: Humans; Biological Transport; Gallium Radioisotopes; Kidney; Liver; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography
PubMed: 35776566
DOI: 10.1259/bjr.20220463 -
European Journal of Nuclear Medicine... Jun 2023Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic... (Review)
Review
INTRODUCTION
Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. METHODS: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15 of July 2022) to search for prospective trials on FAP TRT.
RESULTS
In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD.
CONCLUSION
To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [Lu]Lu-FAPI-04, [Y]Y-FAPI-46, [Lu]Lu-FAP-2286, [Lu]Lu-DOTA.SA.FAPI and [Lu]Lu-DOTAGA.(SA.FAPi). In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.
Topics: Humans; Cell Line, Tumor; Membrane Proteins; Protein Transport; Radioisotopes; Fibroblasts; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes
PubMed: 36813980
DOI: 10.1007/s00259-023-06144-0 -
Journal of Nuclear Medicine : Official... Mar 2022Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide,...
Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-humans results using Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). PTRT using Lu-FAP-2286 was performed on 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary after prior confirmation of uptake on Ga-FAP-2286 or Ga-FAPI-04 PET/CT. Administration of Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective dose was 0.07 ± 0.02 Gy/GBq (range, 0.04-0.1 Gy/GBq). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range, 0.4-2.0 Gy/GBq) and 0.05 ± 0.02 Gy/GBq (range, 0.03-0.09 Gy/GBq), respectively. Significant uptake and long tumor retention of Lu-FAP-2286 resulted in high absorbed tumor doses, such as 3.0 ± 2.7 Gy/GBq (range, 0.5-10.6 Gy/GBq) in bone metastases. No grade 4 adverse events were observed. Grade 3 events occurred in 3 patients-1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up; 3 patients reported a pain response. Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well tolerated, with acceptable side effects, and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.
Topics: Adenocarcinoma; Feasibility Studies; Female; Gallium Radioisotopes; Humans; Peptides; Positron Emission Tomography Computed Tomography; Prospective Studies; Radioisotopes; Tissue Distribution
PubMed: 34168013
DOI: 10.2967/jnumed.120.259192 -
Clinical Cancer Research : An Official... Dec 2022Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been...
PURPOSE
Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response.
EXPERIMENTAL DESIGN
We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer.
RESULTS
[18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses.
CONCLUSIONS
This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy. See related commentary by Weber et al., p. 5241.
Topics: Gelatinases; Serine Endopeptidases; Cell Line, Tumor; Positron-Emission Tomography; T-Lymphocytes; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes
PubMed: 35972732
DOI: 10.1158/1078-0432.CCR-22-1379 -
Journal of Nuclear Medicine : Official... Jun 2022Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted...
Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a Ga-labeled FAPI dimer, Ga-DOTA-2P(FAPI), to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Ga-DOTA-2P(FAPI) was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of Ga-DOTA-2P(FAPI) was evaluated in 3 healthy volunteers, and PET/CT imaging of Ga-FAPI-46 and Ga-DOTA-2P(FAPI) was performed on 3 cancer patients. Ga-DOTA-2P(FAPI) was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of Ga-DOTA-2P(FAPI) was approximately 2-fold stronger than that of Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of Ga-DOTA-2P(FAPI) was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of Ga-DOTA-2P(FAPI) than of Ga-FAPI-46 in all tumor lesions (SUV, 8.1-39.0 vs. 1.7-24.0, respectively; < 0.001). Ga-DOTA-2P(FAPI) has increased tumor uptake and retention properties compared with Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.
Topics: Animals; Gallium Radioisotopes; Humans; Neoplasms; Positron Emission Tomography Computed Tomography; Radiometry; Tissue Distribution; Tumor Microenvironment
PubMed: 34556528
DOI: 10.2967/jnumed.121.263016 -
Journal of Nuclear Medicine : Official... Jun 2022The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not... (Clinical Trial)
Clinical Trial
Head-to-Head Comparison of Ga-PSMA-11 PET/CT and mpMRI with a Histopathology Gold Standard in the Detection, Intraprostatic Localization, and Determination of Local Extension of Primary Prostate Cancer: Results from a Prospective Single-Center Imaging Trial.
The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) ( < 0.001) but not between PSMA PET/CT and mpMRI ( = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE ( = 0.002) and SVI ( = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.
Topics: Gallium Isotopes; Gallium Radioisotopes; Humans; Male; Multiparametric Magnetic Resonance Imaging; Positron Emission Tomography Computed Tomography; Prospective Studies; Prostatic Neoplasms; Reproducibility of Results
PubMed: 34649942
DOI: 10.2967/jnumed.121.262398 -
Journal of Nuclear Medicine : Official... Mar 2023PET imaging that targets fibroblast activation protein (FAP) on the surface of cancer-associated fibroblasts has yielded promising tumor diagnostic results. FAP-2286...
PET imaging that targets fibroblast activation protein (FAP) on the surface of cancer-associated fibroblasts has yielded promising tumor diagnostic results. FAP-2286 contains cyclic peptides as FAP-binding motifs to optimize tumor retention compared with the small-molecule FAP inhibitor (FAPI) series (FAPI-04/46). The aim of this study was to evaluate the diagnostic accuracy of Ga-FAP-2286 to detect primary and metastatic lesions in patients with various types of cancer, compared with F-FDG and Ga-FAP-2286. Sixty-four patients with 15 types of cancer underwent Ga-FAP-2286 PET/CT for initial assessment or detection of recurrence. For comparison, 63 patients underwent paired Ga-FAP-2286 and F-FDG PET/CT and 19 patients underwent paired Ga-FAP-2286 and Ga-FAPI-46 PET/CT. Lesion uptake was quantified as SUV and tumor-to-background ratio. The Wilcoxon matched-pairs signed-rank test was used to compare SUV between PET modalities, and the McNemar test was used to compare lesion detectability. Uptake of Ga-FAP-2286 was significantly higher than that of F-FDG in primary tumors (median SUV, 11.1 vs. 6.9; < 0.001), lymph node metastases (median SUV, 10.6 vs. 6.2; < 0.001), and distant metastases, resulting in improved image contrast and lesion detectability. All primary tumors (46/46) were clearly visualized by Ga-FAP-2286 PET/CT, whereas 9 of the 46 lesions could not be visualized by F-FDG PET/CT. The lesion detection rate of Ga-FAP-2286 PET/CT was superior to that of F-FDG PET/CT for involved lymph nodes (98% [105/107] vs. 85% [91/107], = 0.001) and bone and visceral metastases (95% [162/171] vs. 67% [114/171], < 0.001). Ga-FAP-2286 yielded tumor uptake and lesion detection rates similar to those of Ga-FAPI-46 in a subcohort of 19 patients. Ga-FAP-2286 is a promising FAP-inhibitor derivative for safe cancer diagnosis, staging, and restaging. It may be a better alternative to F-FDG for the cancer types that exhibit low-to-moderate uptake of F-FDG, which include gastric, pancreatic, and hepatic cancers. In addition, Ga-FAP-2286 and Ga-FAPI-46 yielded comparable clinical results.
Topics: Humans; Fluorodeoxyglucose F18; Prospective Studies; Gallium Radioisotopes; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Quinolines; Liver Neoplasms; Cancer-Associated Fibroblasts
PubMed: 36215571
DOI: 10.2967/jnumed.122.264544 -
Nuclear Medicine Review. Central &... 2018Sarcoidosis is a systemic disease of unknown aetiology characterised by the formation of noncaseating granulomas in various organs and tissues. The various imaging... (Review)
Review
Sarcoidosis is a systemic disease of unknown aetiology characterised by the formation of noncaseating granulomas in various organs and tissues. The various imaging modalities that are useful in the investigation of lesions, staging and establishing indications for treatment include: conventional radiography, CT, MRI, and scintigraphy with ⁶⁷Ga, ²⁰¹Tl, 99mTc sestamibi, and somatostatin receptor scintigraphy (SRS) as well as ¹⁸F-FDG-PET/CT. This paper discusses the most commonly used technique of the scintigraphic, gallium (⁶⁷Ga) citrate) and its role in the evaluation and monitoring of patients with sarcoidosis.
Topics: Gallium Radioisotopes; Humans; Organ Specificity; Radionuclide Imaging; Sarcoidosis
PubMed: 29319141
DOI: 10.5603/NMR.a2018.0007 -
Urology Jul 2019
Topics: Gallium Radioisotopes; Humans; Male; Neoplasm Recurrence, Local; Positron-Emission Tomography; Prostatic Neoplasms; Salvage Therapy
PubMed: 31234997
DOI: 10.1016/j.urology.2019.02.035