Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography

Pandya, Darpan N.; Sinha, Akesh; Yuan, Hong; Mutkus, Lysette; Stumpf, Kristina; Marini, Frank C.; Wadas, Thaddeus J.

doi:10.3390/molecules25163672

Cited by 23 publications

(25 citation statements)

References 78 publications

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“…Glioblastoma multiforme (GBM) is the most aggressive glioma of WHO Grade III and IV. Despite the advances in therapeutics, the prognosis for patients remains poor 24 , 25 . FAP was found to be expressed on glioma cells and tumor stroma especially in proximity to blood vessels 26 .…”

Section: Introductionmentioning

confidence: 99%

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics

Wen¹,

Xu²,

Shi³

et al. 2022

Theranostics

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Rationale: Fibroblast activation protein (FAP) targeted molecular imaging radiotracers have shown promising preclinical and clinical results in tumor diagnosis. However, rapid clearance and inadequate tumor retention of these molecules have hindered them for further clinical translation in cancer therapy. In this study, we aimed to develop a series of albumin binder-truncated Evans blue (EB) modified FAP targeted radiotracers, and optimize the pharmacokinetic (PK) characteristics to overcome the existing limitations in order to apply in the radionuclide therapy of cancer. Methods: A series of compounds with the general structure of EB-FAPI-Bn were synthesized based on a FAP inhibitor (FAPI) variant (FAPI-02) and radiolabeled with 177 LuCl 3 . To verify the binding affinity and FAP targeting specificity of these tracers in vitro , U87MG cell uptake and competition assays were performed. Preclinical PK was evaluated in U87MG tumor-bearing mice using SPECT imaging and biodistribution studies. The lead compound EB-FAPI-B1 was selected and cancer therapeutic efficacy of 177 Lu-EB-FAPI-B1 was assessed in U87MG tumor-bearing mice. Results: 177 Lu-EB-FAPI-B1, B2, B3, B4 were stable in PBS (pH 7.4) and saline for at least 24 h. EB-FAPI-B1 showed high binding affinity (IC 50 = 16.5 nM) to FAP in vitro , which was comparable with that of FAPI-02 (IC 50 = 10.9 nM). SPECT imaging and biodistribution studies of 177 Lu-EB-FAPI-B1, B2, B3, B4 have proved their prominently improved tumor accumulation and retention at 96 h post-injection, especially for 177 Lu-EB-FAPI-B1, high tumor uptake and low background signal make it the optimal compound. Compared to the saline group, noteworthy tumor growth inhibitions of 177 Lu-EB-FAPI-B1 have been observed after administration of different dosages. Conclusion: In this study, several EB modified FAPI-02 related radiopharmaceuticals have been synthesized successfully and evaluated. High binding affinity and FAP targeting specificity were identified in vitro and in vivo . Remarkably enhanced tumor uptake and retention of EB-FAPI-B1 were found over the unmodified FAPI-02. 177 Lu-EB-FAPI-B1 showed remarkable tumor growth suppression in U87MG tumor model with negligible side effects, indicating that 177 Lu-EB-FAPI-B1 is promising for clinical application and transformation.

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Section: Introductionmentioning

confidence: 99%

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics

Wen¹,

Xu²,

Shi³

et al. 2022

Theranostics

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“…Recently, Pandya et al updated the mAb F19 antibody with a desferrioxamine (DFO) chelator for the complexation of the positron emitter 89 Zr, which has a half-life suitable for PET imaging with radiolabeled antibodies [ 11 ].…”

Section: Fap Targeting Compoundsmentioning

confidence: 99%

Radioligands Targeting Fibroblast Activation Protein (FAP)

Lindner

Giesel

Kratochwil

et al. 2021

Cancers

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Targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs) has attracted significant attention in nuclear medicine. Since these cells are present in most cancerous tissues and FAP is rarely expressed in healthy tissues, anti-FAP tracers have a potential as pan-tumor agents. Compared to the standard tumor tracer [18F]FDG, these tracers show better tumor-to-background ratios (TBR) in many indications. Unlike [18F]FDG, FAP-targeted tracers do not require exhausting preparations, such as dietary restrictions on the part of the patient, and offer the possibility of radioligand therapy (RLT) in a theragnostic approach. Although a radiolabeled antibody was clinically investigated as early as the 1990s, the breakthrough event for FAP-targeting in nuclear medicine was the introduction and clinical application of the so-called FAPI-tracers in 2018. From then, the development and application of FAP-targeted tracers became hot topics for the radiopharmaceutical and nuclear medicine community, and attracted the interest of pharmaceutical companies. The aim of this review is to provide a comprehensive overview of the development of FAP-targeted radiopharmaceuticals and their application in nuclear medicine.

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“…Due to the unique overexpression and membrane localization of FAP on various cells within the GBM microenvironment, FAP is considered a potential molecular diagnostic biomarker, and FAP inhibitors (FAPIs) have been under investigation for PET imaging in several cancers [ 78 ], broadening the applications for noninvasive tumor diagnosis, grading stratification and planning for surgery and radiotherapy. Both biodistribution studies in U87MG tumor-bearing murine models and small animal PET studies have shown increased immuno-PET radiotracer retention in tumors over time, and the accumulation of radiotracers was a specific marker of FAP expression, indicating that FAP might be a potential imaging biomarker for GBM diagnosis [ 11 ]. Recently, the first in-human clinical pilot study utilizing 68 Ga-FAPI PET further observed increased tracer uptake in IDH-wildtype and IDH-mutant GBM and WHO grade III IDH-mutant astrocytoma but not in WHO grade II astrocytoma [ 24 ].…”

Section: Future Clinical Applications Of Fapmentioning

confidence: 99%

“…In various malignant tumors, FAP is overexpressed and has been demonstrated to participate in tumor growth and progression; therefore, efforts in the clinical translation of FAP have been made, including imaging biomarkers, prognostic value and FAP-targeted therapies [ 8 ]. Recent studies discovered upregulated FAP expression within the GBM microenvironment [ 9 ] and associated FAP expression with tumorigenesis, immunosuppression and chemoresistance in GBM [ 10 , 11 , 12 ]. As an identifying surface marker of cancer-associated fibroblasts (CAFs) in other solid tumors, FAP also assists CAFs in suppressing antitumor immunity, promoting tumor growth and driving epithelial–mesenchymal transition (EMT) [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Oncogenesis, Microenvironment Modulation and Clinical Potentiality of FAP in Glioblastoma: Lessons Learned from Other Solid Tumors

Shi

Kong

Liu

et al. 2021

Cells

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Currently, glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. Fibroblast activation protein (FAP) is a member of the dipeptidyl peptidase family, which has catalytic activity and is engaged in protein recruitment and scaffolds. Recent studies have found that FAP expression in different types of cells within the GBM microenvironment is typically upregulated compared with that in lower grade glioma and is most pronounced in the mesenchymal subtype of GBM. As a marker of cancer-associated fibroblasts (CAFs) with tumorigenic activity, FAP has been proven to promote tumor growth and invasion via hydrolysis of molecules such as brevican in the extracellular matrix and targeting of downstream pathways and substrates, such as fibroblast growth factor 21 (FGF21). In addition, based on its ability to suppress antitumor immunity in GBM and induce temozolomide resistance, FAP may be a potential target for immunotherapy and reversing temozolomide resistance; however, current studies on therapies targeting FAP are still limited. In this review, we summarized recent progress in FAP expression profiling and the understanding of the biological function of FAP in GBM and raised the possibility of FAP as an imaging biomarker and therapeutic target.

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Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography

Cited by 23 publications

References 78 publications

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics

Radioligands Targeting Fibroblast Activation Protein (FAP)

Oncogenesis, Microenvironment Modulation and Clinical Potentiality of FAP in Glioblastoma: Lessons Learned from Other Solid Tumors

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