571P Preclinical evaluation of FAP-2286, a peptide-targeted radionuclide therapy (PTRT) to fibroblast activation protein alpha (FAP)

Zboralski, Dirk; Osterkamp, Frank; Simmons, Andrew; Bredenbeck, Anne; Schumann, Anja; Paschke, Matthias; Beindorff, Nicola; Mohan, Ajay-Mohan; Nguyen, Minh; Xiao, Jim; Harding, Thomas C.; Hoehne, Aileen; Reineke, Ulrich; Smerling, Christiane

doi:10.1016/j.annonc.2020.08.685

Cited by 14 publications

(13 citation statements)

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“…Thirdly, a FAP binding peptide coupled to the radionuclide chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)—which could serve as a potential radiotherapeutic tracer named FAP-2286—was evaluated in both preclinical and clinical levels. FAP-2286 revealed promising data with respect to its potency, selectivity, and efficiency towards FAP [ 19 , 20 ].…”

Section: Fibroblast Activation Protein: a Potential Diagnostic And Therapeutic Target Across Stromal Barriersmentioning

confidence: 99%

“…The targeting of FAP in the tumor stroma using peptide-based radiotracers is still at its outset. By far, there are only two consecutive reports on peptide-targeted radionuclide therapy (PTRT) utilizing FAP as a tumor target [ 19 , 20 ]. FAP-2286 is a FAP-targeted peptidomimetic functionalized with a linker bound to DOTA readily for radiolabeling with 68 Ga for PET imaging or 177 Lu for SPECT imaging and radiotherapy.…”

Section: Development Of Radiolabeled-based Fap Tracers For Tumor Stroma Mediated Nuclear Imaging and Radionuclide-based Therapymentioning

confidence: 99%

“…FAP-2286 is a FAP-targeted peptidomimetic functionalized with a linker bound to DOTA readily for radiolabeling with 68 Ga for PET imaging or 177 Lu for SPECT imaging and radiotherapy. In terms of potency and selectivity, FAP-2286 peptide revealed high affinity within a low nanomolar concentration in both recombinant human FAP protein (~1.1 nM) and cellular FAP-expressing WI 38 fibroblast (~2.7 nM) in vitro [ 19 ]. Moreover, FAP-2286 was further labeled with 177 Lu and its biological behavior was examined in human FAP-transfected HEK 293 and patient-derived sarcoma Sarc4809 xenografts.…”

Section: Development Of Radiolabeled-based Fap Tracers For Tumor Stroma Mediated Nuclear Imaging and Radionuclide-based Therapymentioning

confidence: 99%

“…Furthermore, when the imaging agent that identifies the malignant lesions is followed by the administration of the companion therapeutic agent that treats the same lesions, the generated pair is integrated into the theranostic platform. The visualization of FAP-expressing fibroblasts has been investigated with different diagnostic as well as therapeutic radiolabeled agents, which could be grouped into three main categories: antibodies, FAP inhibitors (FAPIs) of low molecular weight, and peptidomimetic structures [ 15 , 16 , 17 , 18 , 19 , 20 ]. Although imaging of FAP showed great promise in both preclinical studies and clinical trials, the therapeutic efficacy of the fibroblast activation protein inhibitor alone is still limited due to a relatively short retention time of the corresponding radiopharmaceuticals in the tumor area.…”

Section: Introductionmentioning

confidence: 99%

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New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress

et al. 2021

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Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted—as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation.

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Section: Fibroblast Activation Protein: a Potential Diagnostic And Therapeutic Target Across Stromal Barriersmentioning

confidence: 99%

Section: Development Of Radiolabeled-based Fap Tracers For Tumor Stroma Mediated Nuclear Imaging and Radionuclide-based Therapymentioning

confidence: 99%

Section: Development Of Radiolabeled-based Fap Tracers For Tumor Stroma Mediated Nuclear Imaging and Radionuclide-based Therapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress

et al. 2021

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“…Further, genetic depletion of FAP-expressing cells in a subcutaneous model of PDAC permitted immunological control of growth [ 108 ]. Other encouraging FAP targeting strategies using vaccines [ 109 ], FAP antibody-drug conjugates [ 110 ], peptide targeted radionuclide therapy [ 111 ] and CAR-T cells directed at FAP + cells [ 112 ] have also been reported. Early phase trial data evaluating the FAP-specific humanized monoclonal antibody confirmed the safety and tolerability of the agent but with minimal evidence of tumor response.…”

Section: Depletion Of Caf In the Pdac Tmementioning

confidence: 99%

Apoptosis in the Pancreatic Cancer Tumor Microenvironment—The Double-Edged Sword of Cancer-Associated Fibroblasts

Pfeifer

Burchell

Dazzi

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.

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Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

Privé

Boussihmad

Timmermans

et al. 2023

Eur J Nucl Med Mol Imaging

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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 15th 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 [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. 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.

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571P Preclinical evaluation of FAP-2286, a peptide-targeted radionuclide therapy (PTRT) to fibroblast activation protein alpha (FAP)

Cited by 14 publications

References 0 publications

New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress

New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress

Apoptosis in the Pancreatic Cancer Tumor Microenvironment—The Double-Edged Sword of Cancer-Associated Fibroblasts

Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

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