116 results on '"Lückerath, Katharina"'
Search Results
2. Is There a Role of Artificial Intelligence in Preclinical Imaging?
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Küper, Alina, Blanc-Durand, Paul, Gafita, Andrei, Kersting, David, Fendler, Wolfgang P., Seibold, Constantin, Moraitis, Alexandros, Lückerath, Katharina, James, Michelle L., and Seifert, Robert
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- 2023
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3. Fibroblast Activation Protein Inhibitor Theranostics: Preclinical Combination Treatment
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Lückerath, Katharina, Trajkovic-Arsic, Marija, and Mona, Christine E.
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- 2023
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4. Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
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Bicak, Mesude, Lückerath, Katharina, Kalidindi, Teja, Phelps, Michael E., Strand, Sven-Erik, Morris, Michael J., Radu, Caius G., Damoiseaux, Robert, Peltola, Mari T., Peekhaus, Norbert, Ho, Austin, Veach, Darren, Hager, Ann-Christin Malmborg, Larson, Steven M., Lilja, Hans, McDevitt, Michael R., Klein, Robert J., and Ulmert, David
- Published
- 2020
5. Drug and molecular radiotherapy combinations for metastatic castration resistant prostate cancer
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Staniszewska, Magdalena, Iking, Janette, Lückerath, Katharina, Hadaschik, Boris, Herrmann, Ken, Ferdinandus, Justin, and Fendler, Wolfgang P.
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- 2021
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6. 68Ga-FAPi-46 diffuse bilateral breast uptake in a patient with cervical cancer after hormonal stimulation
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Sonni, Ida, Lee-Felker, Stephanie, Memarzadeh, Sanaz, Quinn, Molly M., Mona, Christine E., Lückerath, Katharina, Czernin, Johannes, and Calais, Jeremie
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- 2021
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7. Prognostic value of [18F]FDG-PET/CT in multiple myeloma patients before and after allogeneic hematopoietic cell transplantation
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Stolzenburg, Antje, Lückerath, Katharina, Samnick, Samuel, Speer, Martin, Kneer, Katharina, Schmid, Jan-Stefan, Grigoleit, Götz Ulrich, Hofmann, Susanne, Beer, Ambros J., Bunjes, Donald, Knop, Stefan, Buck, Andreas K., Einsele, Hermann, and Lapa, Constantin
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- 2018
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8. Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities
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Hirmas, Nader, Hamacher, Rainer, Sraieb, Miriam, Ingenwerth, Marc, Kessler, Lukas, Pabst, Kim M., Barbato, Francesco, Lückerath, Katharina, Kasper, Stefan, Nader, Michael, Schildhaus, Hans-Ulrich, Kesch, Claudia, von Tresckow, Bastian, Hanoun, Christine, Hautzel, Hubertus, Aigner, Clemens, Glas, Martin, Stuschke, Martin, Kümmel, Sherko, Harter, Philipp, Lugnier, Celine, Uhl, Waldemar, Niedergethmann, Marco, Hadaschik, Boris, Grünwald, Viktor, Siveke, Jens, Herrmann, Ken, and Fendler, Wolfgang
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Medizin - Published
- 2023
9. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer
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Lückerath, Katharina, Wei, Liu, Fendler, Wolfgang P., Evans-Axelsson, Susan, Stuparu, Andreea D., Slavik, Roger, Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Herrmann, Ken, Radu, Caius G., Czernin, Johannes, and Eiber, Matthias
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- 2018
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10. 18F-PSMA Cerenkov Luminescence and Flexible Autoradiography Imaging in a Prostate Cancer Mouse Model and First Results of a Radical Prostatectomy Feasibility Study in Men.
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Costa, Pedro Fragoso, Püllen, Lukas, Kesch, Claudia, Krafft, Ulrich, Tschirdewahn, Stephan, Moraitis, Alexandros, Radtke, Jan Philipp, Ting, Saskia, Nader, Michael, Wosniack, Jasmin, Kersting, David, Lückerath, Katharina, Herrmann, Ken, Fendler, Wolfgang Peter, Hadaschik, Boris Alexander, and Darr, Christopher
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- 2023
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11. FAPI, PSMA and FDG PET/CT in patients with advanced metastatic castration-resistant prostate cancer (mCRPC) : a triple tracer comparison
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Pabst, K. M., Fendler, Wolfgang P., Hadaschik, Boris, Kesch, C., Hirmas, N., Kessler, Lukas, Gruenwald, V., Hamacher, R., Nader, M., Berliner, C., Umutlu, Lale, Püllen, Lukas, Herrmann, Ken, Lückerath, Katharina, Castellucci, P., Fanti, S., and Mei, R.
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Medizin - Published
- 2022
12. Target Expression and FAP-Directed Tumour Imaging in a Large, Single-Centre PET Database of 324 Patients and 21 Tumour Entities
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Hirmas, N., Ingenwerth, M., Sraieb, Miriam, Kessler, Lukas, Pabst, K. M., Lanzafame, H., Lückerath, Katharina, Kasper, Stefan, Nader, M., Schildhaus, Hans-Ulrich, Hadaschik, Boris, Gruenwald, V., von Tresckow, Bastian, Hanoun, C., Aigner, Clemens, Glas, M., Herrmann, Ken, Siveke, Jens T., Hamacher, R., and Fendler, Wolfgang P.
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Medizin - Published
- 2022
13. Pitfalls and Common Findings in ⁶⁸Ga-FAPI PET : A Pictorial Analysis
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Kessler, Lukas, Ferdinandus, Justin, Hirmas, Nader, Zarrad, Fadi, Nader, Michael, Kersting, David, Weber, Manuel, Kazek, Sandra, Sraieb, Miriam, Hamacher, Rainer, Lückerath, Katharina, Umutlu, Lale, Fendler, Wolfgang, and Rischpler, Christoph
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Medizin - Published
- 2022
14. Nano-coating protects biofunctional materials
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Tscheliessnig, Rupert, Zörnig, Martin, Herzig, Eva M., Lückerath, Katharina, Altrichter, Jens, Kemter, Kristina, Paunel-Görgülü, Adnana, Lögters, Tim, Windolf, Joachim, Pabisch, Silvia, Cinatl, Jindrich, Rabenau, Holger F., Jungbauer, Alois, Müller-Buschbaum, Peter, Scholz, Martin, and Koch, Joachim
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- 2012
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15. Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy
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Lapa, Constantin, Werner, Rudolf A, Bluemel, Christina, Lückerath, Katharina, Schirbel, Andreas, Strate, Alexander, Buck, Andreas K, and Herrmann, Ken
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- 2014
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16. Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain
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Lückerath, Katharina, Kirkin, Vladimir, Melzer, Inga Maria, Thalheimer, Frederic B., Siele, Dagmar, Milani, Wiebke, Adler, Thure, Aguilar-Pimentel, Antonio, Horsch, Marion, Michel, Geert, Beckers, Johannes, Busch, Dirk H., Ollert, Markus, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabĕ de Angelis, Martin, Staal, Frank J.T., Rajalingam, Krishnaraj, Hueber, Anne-Odile, Strobl, Lothar J., Zimber-Strobl, Ursula, and Zörnig, Martin
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- 2011
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17. CXCR4 expression of multiple myeloma as a dynamic process: influence of therapeutic agents.
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Bögelein, Anna, Stolzenburg, Antje, Eiring, Patrick, Lückerath, Katharina, Munawar, Umair, Werner, Rudolf, Schirbel, Andreas, Samnick, Samuel, Kortüm, Klaus Martin, Sauer, Markus, Lapa, Constantin, and Buck, Andreas K.
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CXCR4 receptors ,MULTIPLE myeloma ,CHEMOKINE receptors ,BORTEZOMIB ,CD38 antigen ,ANTINEOPLASTIC agents ,PLASMA cells - Abstract
Chemokine receptors represent novel targets for treatment of multiple myeloma (MM). However, CXCR4 expression appears to be highly dynamic. This in vitro study investigated the impact of commonly used anti-myeloma agents on CXCR4 expression. Established human myeloma cell lines as well as patient-derived CD138
+ plasma cells were exposed to antineoplastic drugs. Cells were analyzed for CXCR4 expression by flow cytometry and direct stochastic optical reconstruction microscopy (dSTORM). In addition, cellular uptake of68 Ga-Pentixafor, a PET radiotracer for noninvasive assessment of CXCR4 expression in vivo, was assessed. CXCR4 expression was highly variable and turned out to be substance, dose and time dependent. Treatment with bortezomib was associated with reduced expression, while dexamethasone and doxorubicin significantly increased expression of CXCR4. Combination of these compounds further increased CXCR4 expression. In conclusion, drugs or combination of drugs can induce CXCR4 expression in myeloma cells. Hence, pretreatment may impact on response to CXCR4-based therapies. [ABSTRACT FROM AUTHOR]- Published
- 2022
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18. PSMA-directed imaging and therapy of salivary gland tumors: a single-center retrospective study.
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Civan, Caner, Kasper, Stefan, Berliner, Christoph, Fragoso-Costa, Pedro, Grünwald, Viktor, Pogorzelski, Michael, Schaarschmidt, Benedikt Michael, Lang, Stephan, Kersting, David, Nader, Michael, Lückerath, Katharina, Herrmann, Ken, Fendler, Wolfgang P., and Weber, Manuel
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- 2022
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19. The gross picture: intraindividual tumour heterogeneity in a patient with nonsecretory multiple myeloma
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Lapa, Constantin, Schirbel, Andreas, Samnick, Samuel, Lückerath, Katharina, Kortüm, K. Martin, Knop, Stefan, Wester, Hans-Jürgen, Buck, Andreas K., and Schreder, Martin
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- 2017
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20. In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma
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Philipp-Abbrederis, Kathrin, Herrmann, Ken, Knop, Stefan, Schottelius, Margret, Eiber, Matthias, Lückerath, Katharina, Pietschmann, Elke, Habringer, Stefan, Gerngro, Carlos, Franke, Katharina, Rudelius, Martina, Schirbel, Andreas, Lapa, Constantin, Schwamborn, Kristina, Steidle, Sabine, Hartmann, Elena, Rosenwald, Andreas, Kropf, Saskia, Beer, Ambros J, Peschel, Christian, Einsele, Hermann, Buck, Andreas K, Schwaiger, Markus, Götze, Katharina, Wester, Hans-Jürgen, and Keller, Ulrich
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- 2015
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21. Immune-Checkpoint Blockade Enhances ²²⁵Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer
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Czernin, Johannes, Current, Kyle, Mona, Christine E., Nyiranshuti, Lea, Hikmat, Firas, Radu, Caius G., and Lückerath, Katharina
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Medizin - Published
- 2021
22. A New Chapter in Neoadjuvant Therapy for High-risk Prostate Cancer?
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Krafft, Ulrich, Hadaschik, Boris A., Lückerath, Katharina, and Herrmann, Ken
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- 2024
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23. Detection Threshold and Reproducibility of ⁶⁸Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer
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Lückerath, Katharina, Stuparu, Andreea D., Wei, Liu, Kim, Woosuk, Radu, Caius G., Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Czernin, Johannes, Slavik, Roger, Herrmann, Ken, Eiber, Matthias, and Fendler, Wolfgang P.
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Medizin - Published
- 2018
24. Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer.
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Stuparu, Andreea D., Capri, Joseph R., Meyer, Catherine A. L., Le, Thuc M., Evans-Axelsson, Susan L., Current, Kyle, Lennox, Mark, Mona, Christine E., Fendler, Wolfgang P., Calais, Jeremie, Eiber, Matthias, Dahlbom, Magnus, Czernin, Johannes, Radu, Caius G., Lückerath, Katharina, and Slavik, Roger
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- 2020
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25. Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer.
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Czernin, Johannes, Current, Kyle, Mona, Christine E., Nyiranshuti, Lea, Hikmat, Firas, Radu, Caius G., and Lückerath, Katharina
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- 2020
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26. Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer.
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Czernin, Johannes, Current, Kyle, Mona, Christine E., Nyiranshuti, Lea, Hikmat, Firas, Radu, Caius G., and Lückerath, Katharina
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- 2020
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27. ¹¹C-methionine-PET in multiple myeloma : Correlation with clinical parameters and bone marrow involvement
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Lapa, Constantin, Knop, Stefan, Schreder, Martin, Rudelius, Martina, Knott, Markus, Jörg, Gerhard, Samnick, Samuel, Herrmann, Ken, Buck, Andreas K., Einsele, Hermann, and Lückerath, Katharina
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Medizin - Abstract
Multiple myeloma (MM) remains an essentially incurable hematologic malignancy originating from clonal plasma cells. This study evaluated the usefulness of the radiotracers ¹¹C-methionine (MET) and ¹⁸F-2'-deoxy-2'-fluorodeoxyglucose (FDG) for staging and re-staging in MM. 43 patients with MM underwent both MET- and FDG-PET/CT for staging or re-staging within 3±2 days. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with the degree of bone marrow (BM) involvement and standard clinical parameters of disease activity. Additionally, BM samples were stained for L-type amino acid transporter 1 (LAT1) expression in 15 patients. MET-PET detected focal lesions (FL) in 39/43 subjects (90.7%), whereas 10 patients were missed in FDG-PET/CT (detection rate, 33/43; 76.7%; p < 0.05). MET depicted more FL in 28/43 patients (65.1%; p < 0.001), whereas in the remainder (34.9%, n=15) both tracers yielded comparable results. LAT1 was highly expressed on the cell surface of myeloma cells. Both FDG and MET uptake correlated significantly with biopsy-proven BM involvement (p < 0.001), with MET demonstrating a stronger correlation (SUVmₑₐn, r=0.9 vs r=0.6; SUVmₐₓ, r=0.88 vs r=0.58). Abnormal beta-2-microglobulin and free light chain levels correlated with the presence of focal intramedullary lesions detected in MET- or FDG-PET/CT (MET, p=0.006 and p=0.01, respectively; FDG, p=0.02 and p=0.01). MET appears to be superior to FDG for staging and re-staging of both intra- and extramedullary MM lesions. Tracer uptake correlates with BM involvement, ß2m and FLC levels and appears to be a more accurate marker of tumor burden and disease activity. CA Extern
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- 2016
28. ¹¹C-Methionine-PET : A novel and sensitive tool for monitoring of early response to treatment in multiple myeloma
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Lückerath, Katharina, Lapa, Constantin, Albert, Christa, Herrmann, Ken, Jörg, Gerhard, Samnick, Samuel, Einsele, Herrmann, Knop, Stefan, and Buck, Andreas K.
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Medizin - Abstract
Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG- μPET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future. CA Extern
- Published
- 2015
29. Potential influence of concomitant chemotherapy on CXCR4 expression in receptor directed endoradiotherapy.
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Lapa, Constantin, Lückerath, Katharina, Kircher, Stefan, Hänscheid, Heribert, Grigoleit, Götz U., Rosenwald, Andreas, Stolzenburg, Antje, Kropf, Saskia, Einsele, Hermann, Wester, Hans‐Jürgen, Buck, Andreas K., Kortüm, Klaus M., and Schirbel, Andreas
- Abstract
Case studies of 32, 62 and 75 years patients are presented with relapsed refractory multiple myeloma, diffuse large B cell lymphoma, and acute lymphoblastic leukaemia. C-X-C-motif chemokine receptor 4 (CXCR4)-directed treatment was offered on a compassionate use basis prior to stem cell transplantation; and initial CXCR4-expression was confirmed in all patients using Pentixafor positron emission tomography/computed tomography and immunohistochemical analysis.
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- 2019
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30. Prognostic value of [18F]FDG-PET/CT in multiple myeloma patients before and after allogeneic hematopoietic cell transplantation.
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Stolzenburg, Antje, Lückerath, Katharina, Samnick, Samuel, Speer, Martin, Kneer, Katharina, Schmid, Jan-Stefan, Grigoleit, Götz Ulrich, Hofmann, Susanne, Beer, Ambros J., Bunjes, Donald, Knop, Stefan, Buck, Andreas K., Einsele, Hermann, and Lapa, Constantin
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MULTIPLE myeloma treatment , *HEMATOPOIETIC stem cell transplantation , *PROGNOSIS , *POSITRON emission tomography , *COMPUTED tomography - Abstract
Purpose: Despite improved treatment options, multiple myeloma (MM) remains an incurable disease. The aim of this study was to investigate the prognostic value of positron emission tomography/computed tomography (PET/CT) using 18F-2’-deoxy-2’-fluorodeoxyglucose ([18F]FDG) in MM patients shortly before and ~100 days after allogeneic hematopoietic cell transplantation (allo-HCT).Methods: In this retrospective analysis, we evaluated [18F]FDG-PET/CT-scans of 45 heavily pre-treated MM patients before and 27 patients after scheduled allo-HCT. All scans were qualitatively and semi-quantitatively assessed for the presence of active disease. Serological response was recorded according to International Myeloma Working Group (IMWG) criteria. Progression-free (PFS) and overall survival (OS) were correlated with different PET/CT-derived parameters, such as presence, number and maximum standardized uptake value (SUVmax) of focal myeloma lesions. The impact of extramedullary disease on patient outcome was also assessed.Results: PET/CT negativity -prior to or following allo-HCT- was a favorable prognostic factor for progression-free and overall survival (both, PFS and OS: pre-HSCT p < 0.001, post-HCT p < 0.005). High FDG-uptake (SUVmax > 6.5) revealed a significantly shortened survival compared to patients with a lower SUVmax (<6.5) (OS, 5.0 ± 1.1 m vs. not reached - longest 122.0 m; p < 0.001). Moreover, our data prove that a higher number (>3) of focal lesions (pre-HCT: both PFS and OS: p < 0.001; post-HCT PFS: p < 0.001, OS: p = 0.139) as well as the presence of extramedullary disease serve as adverse prognostic factors prior to and after allo-HCT. At response assessment after allo-HCT, [18F]FDG-PET/CT had a complementary value in prognostication in addition to IMWG criteria alone.Conclusion: [18F]FDG-PET/CT before and shortly after allogeneic HCT is a powerful predictor for progression-free and overall survival in MM patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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31. Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer.
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Lückerath, Katharina, Stuparu, Andreea D., Liu Wei, Woosuk Kim, Radu, Caius G., Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Czernin, Johannes, Slavik, Roger, Herrmann, Ken, Eiber, Matthias, and Fendler, Wolfgang P.
- Published
- 2018
- Full Text
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32. 18FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation
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Lapa, Constantin, Lückerath, Katharina, Malzahn, Uwe, Samnick, Samuel, Einsele, Herrmann, Buck, Andreas K., Herrmann, Ken, and Knop, Stefan
- Subjects
ddc:610 - Abstract
The aim of this study was to investigate the prognostic value of 18F-fluoro-deoxyglucose positron emission tomography–computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p10 focal lesions correlated with both TTP (p10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p
- Published
- 2014
33. ¹⁸FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation
- Author
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Lapa, Constantin, Lückerath, Katharina, Malzahn, Uwe, Samnick, Samuel, Einsele, Herrmann, Buck, Andreas K., Herrmann, Ken, and Knop, Stefan
- Subjects
Medizin - Abstract
The aim of this study was to investigate the prognostic value of ¹⁸F-fluoro-deoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p10 focal lesions correlated with both TTP (p10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p
- Published
- 2014
34. Establishing 177Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer.
- Author
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Fendler, Wolfgang P., Stuparu, Andreea D., Evans-Axelsson, Susan, Lückerath, Katharina, Liu Wei, Woosuk Kim, Poddar, Soumya, Said, Jonathan, Radu, Caius G., Eiber, Matthias, Czernin, Johannes, Slavik, Roger, and Herrmann, Ken
- Published
- 2017
- Full Text
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35. Analysis of 'knockout, knockin' mice that express a functional Fas Ligand molecule lacking the intracellular domain
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Lückerath, Katharina Maria
- Subjects
ddc:570 ,hemic and immune systems ,chemical and pharmacologic phenomena - Abstract
Fas Ligand (FasL; CD95L; CD178; TNSF6) is a 40 kDa glycosylated type II transmembrane protein with 279 aa in mice and 281 aa in humans that belongs to the tumor necrosis factor (TNF) family. The extracellular domain (ECD) harbors a TNF homology domain, the receptor binding site, a motif for self assembly and trimerization, and several putative N-glycosylation and a metalloprotease cleavage site/s. The cytoplasmic tail of FasL is the longest of all TNFL family members and contains several conserved signaling motifs, such as a putative tandem Casein kinase I phosphorylation site, a unique proline-rich domain (PRD) and phosphorylatable tyrosine residues (Y7 in mice; Y7, Y9, Y13 in human). The FasL/Fas system is renowned for the potent induction of apoptosis in the receptor-bearing cell and is especially important for immune system functions. It is involved in the killing of target cells by natural killer (NK) and cytotoxic T cells, in the (self) elimination of effector cells following the proliferative phase of an immune response (activation-induced cell death; AICD), in the maintenance of immuneprivileged sites and in the induction and maintenance of peripheral tolerance. Owing to its potent pro-apoptotic signaling capacity and important functions, FasL expression and activity are tightly regulated at transcriptional and posttranscriptional levels and restricted to few cell types, such as immune effector cells and cells of immune-privileged sites. In contrast, Fas is expressed in a variety of tissues including lymphoid tissues, liver, heart, kidney, pancreas, brain and ovary. In addition to its pro-apoptotic function, the FasL/Fas system can also elicit nonapoptotic signals in the receptor-expressing cell. Among others, Fas-signaling exerts co-stimulatory functions in the immune system, e.g. by promoting survival, activation and proliferation of T cells. Besides the capacity to deliver a signal into receptor-bearing cells (‘forward signal’), FasL can receive and transmit signals into the ligand-expressing cell. This phenomenon has been described for several TNF family ligands and is known as ‘reverse signaling’. The first evidence for the existence of reverse signaling into FasL-bearing cells stems from two studies that demonstrated either co-stimulation of murine CD8+ T cell lines by FasL cross-linking or inhibition of activation-induced proliferation of murine CD4+ T cells. In both cases, the observed changes of proliferative behaviour critically depended on the presence of a signaling-competent FasL. Almost certainly, the FasL ICD is functionally involved in signal-transmission: (i) The ICD is highly conserved across species and harbors several signaling motifs, most notably a unique PRD. (ii) Numerous proteins have been identified which interact with the FasL PRD via their SH3 or WW domains and regulate various aspects of FasL biology, such as FasL sorting, storage, cell surface expression and the linkage of FasL to intracellular signaling pathways. (iii) Post-translational modifications of the ICD have been implicated in the sorting of FasL to vesicles and the FasL-dependent activation of Nuclear factor of activated T cells (NFAT). (iv) Proteolytic processing of FasL liberates the ICD and allows its translocation into the nucleus where it might influence gene transcription. (v) It could be shown that overexpression of the FasL ICD is sufficient to initiate reverse signaling upon concomitant T cell receptor (TCR) stimulation and ICD cross-linking. Conflicting data on the consequences of FasL reverse signaling exist, and costimulatory as well as inhibitory functions have been reported. These discrepancies probably reflect the use of artificial experimental systems. Neither the precise molecular mechanism underlying FasL reverse signaling, nor its physiological relevance have been addressed at the endogenous protein level in vivo. Therefore, a ‘knockout/knockin’ mouse model in which wildtype FasL was replaced with a deletion mutant lacking the intracellular portion (FasL Delta Intra) was established in the group of PD Dr. Martin Zörnig. In the present study, FasL Delta Intra mice were phenotypically characterized and were employed to investigate the physiological consequences of FasL reverse signaling at the molecular and cellular level. To ensure that FasL Delta Intra mice represent a suitable model to study the consequences of FasL reverse signaling, we demonstrated that activated lymphocytes from homozygous FasL Delta Intra or wildtype mice express comparable amounts of (truncated) FasL at the cell surface. The truncated protein retains the capacity to induce apoptosis in Fas receptor-positive target cells, as co-culture assays with FasL-expressing activated lymphocytes and Fas-sensitive target cells showed. Additionally, systematic screening of unchallenged mice did not reveal any phenotypic abnormalities. Notably, signs of a lymphoproliferative autoimmune disease associated with FasL-deficiency could not be detected. As several reports have implicated FasL reverse signaling in the regulation of T cell expansion and activation, proliferation of lymphocytes isolated from FasL Delta Intra and wildtype mice in response to antigen receptor stimulation was investigated. Using CFSE dilution assays it could be demonstrated that the proliferative response of CD4+ T cells, CD8+ T cells and of B cells was enhanced in the absence of the FasL ICD. Interestingly, this effect was most pronounced in B cells and could only be detected in CD4+ T cells after depletion of CD4+CD25+ regulatory T cells. To our Summary knowledge, this is the first time that FasL reverse signaling has been demonstrated in B cells. In a series of experiments, the activation of several pathways that are known to play important roles in signal-transmission initiated upon antigen receptor triggering was assessed. As a molecular correlate for the observed enhancement of activation-induced proliferation, Extracellular signal regulated kinase (ERK1/2) phosphorylation was significantly increased in FasL Delta Intra mice following antigen receptor crosslinking. Surprisingly, B cell stimulation lead to a comparable extent of activating phosphorylations on S38 in c-Raf and S218/S222 in MEK1/2 in cells isolated from wildtype and FasL Delta Intra mice, indicating that Mitogen activated protein kinases (MAPKs) upstream of ERK1/2 (Raf-1 and MEK1/2) apparently do not contribute to the differential regulation of ERK1/2. Experiments in which activation-induced Akt phosphorylation (S473) was quantified also did not suggest a participation of Phosphoinositol specific kinase 3 (PI3K)/Akt signals in this process. Instead, further characterization of the upstream pathway revealed an involvement of Phospholipase C gamma (PLC gamma) and Protein kinase C (PKC) signals in FasL-dependent ERK1/2- regulation. Previous studies in our group revealed a Notch-like processing of FasL, resulting in the transcriptional regulation of a reporter gene. Furthermore, an interaction of the FasL ICD with the transcription factor Lymphoid-enhancer binding factor-1 (Lef-1) that affected Lef-1-dependent reporter gene transcription could be demonstrated. Therefore, a molecular analysis of activated lymphocytes was performed to identify FasL reverse signaling target genes. The differential expression of promising candidates was verified by quantitative real-time PCR (qRT-PCR), which showed that the transcription of genes associated with lymphocyte proliferation and activation was increased in FasL Delta Intra mice compared to wildtype mice. Interestingly, an extensive regulation of Lef-1-dependent Wnt/beta-Catenin signalingrelated genes was found. Lef-1 mRNA (RT-PCR) and protein (intracellular FACS staining) could be detected in mature B cells, suggesting the possibility of FasL ICD-mediated inhibition of Lef-1-dependent gene expression in these cells, initiated by Notch-like processing of FasL. To investigate the consequences of FasL reverse signaling in vivo, a potential participation of the FasL ICD in the regulation of immune responses upon various challenges was analyzed. In experiments in which thymocyte proliferation or the expansion of antigen-specific T cells following a challenge with the superantigen Staphylococcus enterotoxin B (SEB), with Lymphocytic choriomeningitis virus (LCMV) or with Listeria monocytogenes were investigated, comparable results were obtained with wildtype and FasL Delta Intra mice. Likewise, the recruitment of neutrophils in a thioglycollate-induced model of peritonitis was not affected by deletion of the FasL ICD. These findings might reflect regulatory mechanisms operating in vivo, such as control exerted by regulatory T cells. Along these lines, proliferative differences in CD4+ T cells could only be detected ex vivo after depletion of CD4+CD25+ regulatory T cells. Furthermore, several in vitro studies indicate that retrograde FasL signals can be observed under conditions of suboptimal lymphocyte stimulation, but not when the TCR is optimally stimulated. Therefore, the potent initiation of antigen receptor signaling by stimuli like SEB or LCMV might have masked inhibitory FasL reverse signaling in these experiments. In agreement with the observed hyperactivation of lymphocytes in the absence of the ICD ex vivo, the increase in germinal center B cells (GCs) following immunization with the hapten 3-hydroxy 4-nitrophenylacetyl (NP) and the number of antibody-secreting PCs was significantly higher in FasL Delta Intra mice. The larger quantity of PCs correlated with increased titers of NP-binding, i.e. antigen-specific, IgM and IgG1 antibodies in the serum of FasL Delta Intra mice after immunization. These data suggest that FasL reverse signaling exerts immunmodulatory functions. Supporting this notion, a model of Ovalbumin-induced allergic airway inflammation revealed an involvement of retrograde FasL-signals in the recruitment of immune effector cells into the lung and in the activation of T cells following exposure of mice to Ovalbumin. Together, our ex vivo and in vivo findings based on endogenous FasL protein levels demonstrate that FasL ICD-mediated reverse signaling is a negative modulator of certain immune responses. It is tempting to speculate that FasL reverse signaling might be a fine-tuning mechanism to prevent autoimmune diseases, a theory which will be tested in adequate mouse models in the future. Der Fas Ligand (FasL; CD95L; CD178; TNSF6) ist ein glykosyliertes Typ II Transmembranprotein, das zur Proteinfamilie der Tumornekrosefaktor (TNF)-Liganden gehört. Das Mausprotein besteht aus 279 Aminosäuren, während der humane FasL 281 Aminosäuren umfasst. Im extrazellulären Teil des Liganden befinden sich eine TNF Homologie-Domäne, die Rezeptorbindestelle, ein Sequenzmotiv zur Selbstaggregation und Trimerisierung sowie mehrere Stellen, an denen der FasL N-glykosyliert oder von Metalloproteasen geschnitten werden kann. Die intrazelluläre Region des FasL ist die längste aller TNFL-Familienmitglieder und enthält verschiedene konservierte Signalmotive, z.B. ein Casein-Kinase I (CK-I) Substrat-Motiv, eine Prolin-reiche Domäne (PRD) und potentielle Tyrosin-Phosphorylierungsstellen (Maus: Y7; Mensch: Y7, Y9, Y13). Die Bindung des FasL an den zugehörigen Rezeptor Fas löst in der rezeptortragenden Zelle apoptotischen Zelltod aus. Dies spielt eine besondere Rolle für verschiedenen Funktionen des Immunsystems, z.B. für die Lyse von Zielzellen durch natürliche Killerzellen (NK-Zellen) und zytotoxische T-Zellen, für die Selbsteliminierung von Effektorzellen nach der Expansionsphase einer Immunantwort (activation-induced cell death; AICD), für die Aufrechterhaltung eines immunprivilegierten Status bestimmter Gewebe und für die Induktion und Erhaltung der peripheren Toleranz. Im Gegensatz zu dem von vielen Zelltypen konstitutiv exprimiertem Fas-Rezeptor ist die Expression und Aktivität des FasL auf wenige Zelltypen beschränkt (Zellen des Immunsystems und immunprivilegierte Gewebe) und wird auf transkriptioneller und post-translationaler Ebene reguliert. Ebenso wichtig wie die pro-apoptotische Funktion ist die Vermittlung nichtapoptotischer Signale durch den Fas-Rezeptor. So wurde unter anderem gezeigt, dass Fas-Aktivierung ko-stimulatorisch wirken und das Überleben, die Aktivierung und die Proliferation von T-Zellen und Tumorzellen fördern kann. Zusätzlich zu der Vermittlung des klassischen „Vorwärtssignals“ in die rezeptortragende Zelle kann FasL selbst Signale empfangen und in die ligandexprimierende Zelle weiterleiten. Dieses Phänomen wird als „reverse“ oder „bidirektionale“ Signalübertragung bezeichnet und wurde ebenfalls für andere TNFL-Familienmitglieder beschrieben. Erste Hinweise für die Existenz einer reversen Signalübertragung in die FasL-tragende Zelle stammen aus zwei Studien, in denen gezeigt wurde, dass die Vernetzung des FasL durch Fas-Fc oder anti-FasL-Antikörper die T-Zell-Rezeptor (TZR)-vermittelte Proliferation muriner CD8+ T-Zelllinien ko-stimuliert bzw. die muriner CD4+ T-Zellen inhibiert. In beiden Fällen hingen die beobachteten Veränderungen des Proliferationsverhaltens von der Anwesenheit eines funktionellen Liganden ab. Es ist anzunehmen, dass das retrograde Signal durch die intrazelluläre Domäne (IZD) des FasL vermittelt wird: (i) Die IZD ist speziesübergreifend konserviert und beinhaltet mehrere Signalmotive, darunter eine innerhalb der TNFL-Familie einzigartige PRD. (ii) Eine Vielzahl von Proteinen bindet über eine SH3 oder WW Domäne an die PRD des FasL und reguliert so verschiedene Aspekte der FasL-Biologie, wie z.B. die subzelluläre Lokalisation, die Expression an der Zelloberfläche und das Zusammenspiel mit intrazellulären Signalwegen. (iii) Post-translationale Modifikationen der IZD wurden mit der Sortierung des Liganden in Vesikel und der FasL-abhängigen Aktivierung von Nuclear factor of activated T cells (NFAT) in Verbindung gebracht. (iv) Die proteolytische Prozessierung des FasL führt zur Freisetzung der IZD in das Zytosol und ermöglicht die Translokation der IZD in den Zellkern, wo sie die Transkription von Genen regulieren kann. (v) Es konnte gezeigt werden, dass die Überexpression der FasL IZD ausreicht, um nach gleichzeitiger TZR-Stimulation und IZD-Vernetzung eine reverse Signalübertragung in murinen CD8+ T-Zelllinien zu initiieren. Die möglichen Konsequenzen der FasL-vermittelten reversen Signalübertragung werden kontrovers diskutiert, und sowohl ko-stimulatorische wie auch inhibitorische Funktionen sind publiziert worden. Diese sich widersprechenden Beobachtungen basieren vermutlich darauf, dass die Experimente in artifiziellen Systemen durchgeführt wurden und weder der molekulare Mechanismus, noch die physiologische Bedeutung der reversen Signalübertragung auf der Ebene des endogenen Proteins in vivo untersucht wurden. Daher wurde in der Arbeitsgruppe von PD Dr. Martin Zörnig ein Mausmodell für eine defekte reverse FasL Signalübertragung (FasL Delta Intra) etabliert. Diesen ‚knockout/knockin’-Mäusen fehlt die intrazelluläre FasL Domäne, während die Transmembran- und die extrazelluläre Domäne weiterhin vorhanden sind. Im Verlauf der vorliegenden Arbeit wurden die FasL Delta Intra Mäuse phänotypisch charakterisiert und als Modell genutzt, um die physiologische Funktion der reversen FasL Signalübertragung auf molekularer und zellulärer Ebene aufzuklären. Um sicherzustellen, dass die FasL Delta Intra Mäuse ein geeignetes Modellsystem zur Analyse der reversen FasL Signalübertragung darstellen, wurden die Expression und Funktionalität des trunkierten FasL untersucht. Die korrekte Ausführung FasL/Fas-vermittelter Apoptose ist ein wichtiger Punkt, da natürlich vorkommende Maus-Mutantenstämme, in denen die Fas-induzierte Apoptose durch Mutationen im FasL (FasLgld/gld) bzw. im Fas (Faslpr/lpr) Gen inaktiviert wird, eine schwere Autoimmunerkrankung entwickeln. Ein vergleichbarer Phänotyp in FasL Delta Intra Mäusen könnte die Auswirkungen der defekten reversen Signalübertragung maskieren. Die Expression des FasL konnte durch RT-PCR und durchflußzytometrische Färbungen auf der Oberfläche aktivierter Lymphozyten in homozygoten FasL Delta Intra Mäusen verifiziert werden. Experimente, in denen aktivierte Lymphozyten mit Fas-sensitiven Zielzellen ko-kultiviert wurden, zeigten, dass der trunkierte FasL weiterhin Apoptose in Fas-tragenden Zellen auslösen kann. Außerdem weisen die FasL Delta Intra Mäuse im gesunden Zustand keinerlei phänotypische Auffälligkeiten auf und entwickeln keine Symptome der mit FasL-Defizienz (FasL gld/gld, FasL-/-) verbundenen lymphoproliferativen Autoimmunerkrankung. Da die meisten Studien eine Beeinflussung der T-Zell Expansion durch die reverse FasL Signalübertragung nahe legen, wurde das Proliferationsverhalten von Lymphozyten aus homozygoten FasL Delta Intra oder Wildtyp Mäusen nach Stimulation des jeweiligen Antigenrezeptors analysiert. Experimente zur aktivierungsinduzierten Lymphozytenexpansion belegten eine deutlich höhere Proliferationskapazität von einzelpositiven CD4+ und CD8+ T-Zellen sowie B-Zellen ohne IZD. Dieser Effekt war in B-Zellen am stärksten ausgeprägt und konnte in CD4+ T-Zellen nur dann beobachtet werden, wenn zuvor regulatorische CD4+CD25+ T-Zellen (Tregs) depletiert wurden. Nach unserem Kenntnisstand beschreibt die vorliegende Arbeit zum ersten Mal die Auswirkungen der reverse FasL Signalübertragung in B-Zellen. Um zu verstehen, wie reverses FasL-Signaling auf aktivierungsinduzierte Lymphozytenproliferation einwirkt, wurde das Anschalten verschiedener Signalwege, die bekanntermaßen für die vom Antigenrezeptor ausgehende Signalverarbeitung wichtig sind, untersucht. Als ein molekulares Korrelat für die beobachtete verstärkte Proliferation wurde eine deutlich erhöhte Phosphorylierung der Extracellular signal regulated kinase (ERK1/2) nach Vernetzung des Antigerezeptors in homozygoten FasL Delta Intra Mäusen gefunden. Überraschenderweise schienen die ERK1/2-vorgeschalteten Mitogen-aktivierten Proteinkinasen (MAPKs) Raf-1 und MEK1/2 nicht für die differentielle Regulation von ERK1/2 verantwortlich zu sein, da die Stimulation von Wildtyp und FasL-mutanten B-Zellen zu einem vergleichbaren Ausmaß aktivierender Phosphorylierungen in c-Raf1 (S38) und MEK1/2 (S218/S222) führte. Ebenso wiesen Experimente, in denen die aktivierungsinduzierte Akt-Phosphorylierung (S473) untersucht wurde, nicht auf eine Beteiligung des Phosphoinositol-spezifische Kinase 3 (PI3K)/Akt Signalwegs an der reversen FasL Signalübertragung hin. Es konnte jedoch gezeigt werden, dass durch Phospholipase C gamma (PLC gamma) und Proteinkinase C (PKC) vermittelte Signale in die FasL-abhängige Regulation von ERK1/2 involviert sind. Unsere Gruppe konnte zeigen, dass FasL in einer ähnlichen Weise wie das Signalprotein Notch prozessiert wird. Dies führt nach proteolytischer Freisetzung der FasL IZD in das Zytoplasma zur transkriptionellen Regulation eines Reportergens. Des Weiteren wurde in der Arbeitsgruppe von PD Dr. M. Zörnig eine Interaktion der FasL IZD mit dem Transkriptionsfaktor Lymphoid-enhancer binding factor-1 (Lef-1) aufgezeigt, die die Lef-1-abhängige Transkription beeinflusste. Daher wurde im Rahmen dieser Doktorarbeit eine systematische Expressionsanalyse aktivierter Lymphozyten durchgeführt. Die dabei identifizierten Zielgene der reversen FasL Signalübertragung wurden durch quantitative real-time PCR (qRT-PCR) verifiziert. Es stellte sich heraus, dass vor allem Gene, die mit der Proliferation und Aktivierung von Lymphozyten assoziiert werden, in homozygoten FasL Delta Intra Mäusen stärker exprimiert werden. Interessanterweise wurde ebenfalls eine extensive Regulation von Genen, die mit Lef-1-abhängigen Wnt/beta-Catenin-Signalen im Zusammenhang stehen, beobachtet. Obwohl andere Publikationen nahe legen, dass die Expression von Lef-1 während der B-Zell-Entwicklung stark herunterreguliert wird, konnten in der vorliegenden Arbeit Lef-1 mRNA (RT-PCR) und Protein (intrazelluläre, durchflußzytometrische Färbung) in naïven B-Zellen detektiert werden. Diese Daten weisen auf einen Zusammenhang von reverser FasL Signalübertragung und Lef-1 in reifen Lymphozyten hin. Zur Aufklärung der in vivo Funktion reverser FasL Signalübertragung wurden verschiedene Infektions- und Immunisierungsmodelle angewendet, mit denen eine mögliche Beteiligung der FasL IZD an der Regulation von Immunantworten untersucht werden kann. Experimente, in denen die Thymozytenproliferation oder die Expansion Antigen-spezifischer T-Zellen in Folge einer Infektion mit dem Superantigen Staphylococcus enterotoxin B (SEB), mit dem Lymphozyten Choriomeningitis Virus (LCMV) oder dem intrazellulären Bakterium Listeria monocytogenes evaluiert wurden, ergaben vergleichbare Ergebnisse in Wildtyp und FasL Delta Intra Mäusen. Auch die Rekrutierung von Neutrophilen in einem Thioglycollat-induzierten Peritonitismodell wurde nicht von der Deletion der FasL IZD beeinflußt. Möglicherweise spiegeln diese Befunde in vivo aktive, regulatorische Mechanismen wider, wie z.B. eine durch regulatorische T-Zellen ausgeübte Kontrolle. Ein Hinweis darauf ist die ex vivo Beobachtung, dass Unterschiede in der Proliferation von Wildtyp und mutanten CD4+ T-Zellen nur beobachtet werden konnten, wenn regulatorische T-Zellen vorher depletiert wurden. Außerdem zeigen verschiedene in vitro Studien, dass retrograde FasL-Signale nur bei sub-optimaler Lymphozyten-Stimulation beobachtet werden können, nicht aber bei optimaler Vernetzung des TZR. Daher könnten Stimuli wie SEB oder LCMV durch die starke Initiation von Antigenrezeptorsignalen die inhibitorische Funktion der reverse FasL Signaltransduktion maskieren. Im Einklang mit der ex vivo beobachteten Hyperaktivierung von Lymphozyten ohne FasL IZD wurden in FasL Delta Intra Mäusen nach Immunisierung mit dem Antigen 3- hydroxy 4-nitrophenylacetyl (NP) signifikant mehr Keimzentrums-B-Zellen gebildet. Ein erhöhter prozentualer Anteil Plasmazellen in der Milz von FasL Delta Intra Mäuse korrelierte mit signifikant höheren Titern NP-bindender, d.h. Antigen-spezifischer IgM- und IgG1-Antikörper im Serum. Diese Befunde deuten darauf hin, dass die reverse Signalübertragung via FasL immunmodulatorische Funktionen ausübt. Damit übereinstimmend konnte in einem Model der Ovalbumin-induzierten allergischen Atemwegsentzündung gezeigt werden, dass retrograde FasL Signale den Krankheitsverlauf durch Verminderung der Immuneffektorzellrekrutierung und Verstärkung der T-Zell Aktivierung abmildern. Die hier beschriebenen, auf endogenem Proteinniveau erhaltenen, ex vivo und in vivo Befunde zeigen, dass die reverse Signalübertragung durch die FasL IZD unter bestimmten Bedingungen immunmodulatorische Funktionen übernimmt. Dabei könnte die reverse FasL Signalübertragung ein Mechanismus zur Termination und Feinabstimmung von Immunantworten sein, der zur Prävention von Autoimmunerkrankungen beiträgt. Zukünftige Studien an geeigneten Mausmodellen für Autoimmunerkrankungen werden diese Möglichkeit untersuchen.
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- 2010
36. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging.
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Fecher, David, Hofmann, Elisabeth, Buck, Andreas, Bundschuh, Ralph, Nietzer, Sarah, Dandekar, Gudrun, Walles, Thorsten, Walles, Heike, Lückerath, Katharina, and Steinke, Maria
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LUNG tumors ,DRUG development ,EXTRACELLULAR matrix ,TREATMENT of lung tumors ,POSITRON emission tomography ,LONGITUDINAL method ,DIAGNOSIS - Abstract
Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[
18 F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. [ABSTRACT FROM AUTHOR]- Published
- 2016
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37. First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.
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Herrmann, Ken, Schottelius, Margret, Lapa, Constantin, Osl, Theresa, Poschenrieder, Andreas, Hänscheid, Heribert, Lückerath, Katharina, Schreder, Martin, Bluemel, Christina, Knott, Markus, Keller, Ulrich, Schirbel, Andreas, Samnick, Samuel, Lassmann, Michael, Kropf, Saskia, Buck, Andreas K., Einsele, Hermann, Wester, Hans-Juergen, and Knop, Stefan
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- 2016
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38. [11C]Methionine emerges as a new biomarker for tracking active myeloma lesions.
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Lapa, Constantin, Schreder, Martin, Lückerath, Katharina, Samnick, Samuel, Rudelius, Martina, Buck, Andreas K., Kortüm, Klaus M., Einsele, Hermann, Rosenwald, Andreas, and Knop, Stefan
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METHIONINE ,BIOMARKERS ,PRECANCEROUS conditions ,MULTIPLE myeloma ,AMINO acids ,POSITRON emission tomography - Abstract
The article discusses a prospective study which investigated the emergence of L-methyl-C methionine (MET) as a new biomarker for monitoring active myeloma lesions. Involved in the study were ten patients with biopsy-proven multiple myeloma who underwent molecular imaging using positron emission tomography (PET) with a radiolabelled glucose analogue for diagnosis. The study has shown the potential superiority of the amino acid MET for staging multiple myeloma.
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- 2018
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39. Tumor-Associated Macrophages in Glioblastoma Multiforme—A Suitable Target for Somatostatin Receptor-Based Imaging and Therapy?
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Lapa, Constantin, Linsenmann, Thomas, Lückerath, Katharina, Samnick, Samuel, Herrmann, Ken, Stoffer, Carolin, Ernestus, Ralf-Ingo, Buck, Andreas K., Löhr, Mario, and Monoranu, Camelia-Maria
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GLIOBLASTOMA multiforme ,SOMATOSTATIN ,TARGETED drug delivery ,TUMOR growth ,GENE expression - Abstract
Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM. Methods: 15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using
68 Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry. Results: The amount of microglia/macrophages ranged from <10% to >50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns. Conclusion: SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM. [ABSTRACT FROM AUTHOR]- Published
- 2015
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40. Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer.
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Staniszewska, Magdalena, Fragoso Costa, Pedro, Eiber, Matthias, Klose, Jasmin M., Wosniack, Jasmin, Reis, Henning, Szarvas, Tibor, Hadaschik, Boris, Lückerath, Katharina, Herrmann, Ken, Fendler, Wolfgang P., and Iking, Janette
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CASTRATION-resistant prostate cancer ,COMPUTED tomography ,PROSTATE cancer ,POSITRON emission tomography ,OVERALL survival - Abstract
Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of PSMA and androgen receptor (AR) expression on the human PC cell lines 22Rv1, C4-2, and LNCaP by immunohistochemistry and flow cytometry revealed low (22Rv1) and high (C4-2 and LNCaP) PSMA expression, and high, comparable AR positivity. Treatment with enzalutamide increased PSMA levels in 22Rv1, C4-2, and LNCaP (2.2/2.3/2.6-fold, p = 0.0005/0.03/0.046) after one week compared to DMSO-treated controls as assessed by flow cytometry. NOD/Scid mice bearing 22Rv1 tumors were treated with enzalutamide for two weeks. Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of
68 Ga-PSMA after enzalutamide treatment (p = 0.004). Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of68 Ga-PSMA after enzalutamide on PET/CT and post-therapeutic177 Lu-PSMA scintigraphy in a patient with mCRPC. Enzalutamide induced PSMA expression in the 22Rv1 xenograft model and in an mCRPC patient, both with low baseline tumoral PSMA levels. Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for177 Lu-PSMA RLT. [ABSTRACT FROM AUTHOR]- Published
- 2021
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41. Imaging Inflammation with Positron Emission Tomography.
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Iking, Janette, Staniszewska, Magdalena, Kessler, Lukas, Klose, Jasmin M., Lückerath, Katharina, Fendler, Wolfgang P., Herrmann, Ken, Rischpler, Christoph, and Oriuchi, Noboru
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POSITRON emission tomography ,PROGNOSIS ,INFLAMMATION ,CARDIOVASCULAR diseases ,RADIOACTIVE tracers - Abstract
The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings. [ABSTRACT FROM AUTHOR]
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- 2021
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42. Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology.
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Lückerath, Katharina, Lapa, Constantin, Spahmann, Annika, Jörg, Gerhard, Samnick, Samuel, Rosenwald, Andreas, Einsele, Herrmann, Knop, Stefan, and Buck, Andreas K.
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MULTIPLE myeloma diagnosis , *BIOSYNTHESIS , *GENE targeting , *PROTEIN synthesis , *PLASMA cells , *HEMATOLOGIC malignancies , *NONINVASIVE diagnostic tests , *POSITRON emission tomography - Abstract
Purpose:Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. Experimental Design:To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features. Results:Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET. Conclusion:These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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43. Evaluating [225Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.
- Author
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Taddio, Marco F., Doshi, Suraj, Masri, Marwan, Jeanjean, Pauline, Hikmat, Firas, Gerlach, Alana, Nyiranshuti, Lea, Rosser, Ethan W., Schaue, Dorthe, Besserer-Offroy, Elie, Carlucci, Giuseppe, Radu, Caius G., Czernin, Johannes, Lückerath, Katharina, and Mona, Christine E.
- Abstract
Purpose: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB.[68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept.[225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment.[225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.Methods: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB.[68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept.[225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment.[225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.Results: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB.[68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept.[225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment.[225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.Conclusion: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB.[68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept.[225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment.[225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. Chemokine receptor – Directed imaging and therapy.
- Author
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Buck, Andreas K., Stolzenburg, Antje, Hänscheid, Heribert, Schirbel, Andreas, Lückerath, Katharina, Schottelius, Margret, Wester, Hans-Jürgen, and Lapa, Constantin
- Subjects
- *
CHEMOKINE receptors , *LIGAND field theory , *CELL migration , *BONE marrow , *HEMATOPOIETIC stem cells , *NEOVASCULARIZATION - Abstract
The C-X-C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation. The CXCR4/CXCL12 interplay can be disrupted by CXCR4 antagonists such as Plerixafor which are already in daily clinical use, i.e. for mobilization and subsequent harvesting of hematopoietic progenitor cells and stem cell transplantation. In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases. Recently, radiolabeled analogs of CXCR4 antagonists (e.g., [ 68 Ga]Pentixafor) have been introduced which can be used for non-invasive imaging of CXCR4 expression in animal models and humans using positron emission tomography. In addition, beta emitter-labeled antagonists (i.e., [ 177 Lu]/[ 90 Y]Pentixather) have been used in small patient cohorts for treatment of hematological neoplasms such as lymphoma, multiple myeloma and acute myeloid leukemia. This review reports on current imaging protocols for CXCR4-directed positron emission tomography in preclinical models and in humans. Furthermore, a theranostic approach using beta emitter-labeled antagonists is highlighted. Molecular imaging of the CXCR4/CXCL12 axis can contribute to further understand the process of metastatic spread and the intra-/interindividual heterogeneity of tumors. In addition, CXCR4 directed imaging allows tracking of activated, CXCR4 + immune cells. This allows for watching inflammatory processes, thus contributing to enlighten the role of the immune system in a variety of cardiovascular and neurological diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
45. Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.
- Author
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Storey CM, Altai M, Bicak M, Veach DR, Lückerath K, Adrian G, McDevitt MR, Kalidindi T, Park JE, Herrmann K, Abou D, Zedan W, Peekhaus N, Klein RJ, Damoiseaux R, Larson SM, Lilja H, Thorek D, and Ulmert D
- Subjects
- Animals, Humans, Male, Mice, Cell Line, Tumor, Positron Emission Tomography Computed Tomography, Receptors, Androgen genetics, Receptors, Androgen metabolism, Zirconium, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms genetics, Prostatic Neoplasms radiotherapy, Radioisotopes
- Abstract
Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels., Implications: hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted., (©2023 American Association for Cancer Research.)
- Published
- 2023
- Full Text
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46. 18 F-PSMA Cerenkov Luminescence and Flexible Autoradiography Imaging in a Prostate Cancer Mouse Model and First Results of a Radical Prostatectomy Feasibility Study in Men.
- Author
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Costa PF, Püllen L, Kesch C, Krafft U, Tschirdewahn S, Moraitis A, Radtke JP, Ting S, Nader M, Wosniack J, Kersting D, Lückerath K, Herrmann K, Fendler WP, Hadaschik BA, and Darr C
- Subjects
- Humans, Male, Animals, Mice, Positron Emission Tomography Computed Tomography methods, Positron-Emission Tomography methods, Autoradiography, Luminescence, Feasibility Studies, Gallium Radioisotopes, Prostatectomy methods, Prostate diagnostic imaging, Prostate surgery, Prostate pathology, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms surgery, Prostatic Neoplasms pathology
- Abstract
Intraoperative identification of positive resection margins (PRMs) in high-risk prostate cancer (PC) needs improvement. Cerenkov luminescence imaging (CLI) with
68 Ga-PSMA-11 is promising, although limited by low residual activity and artificial signals. Here, we aimed to assess the value of CLI and flexible autoradiography (FAR) with18 F-PSMA-1007. Methods: Mice bearing subcutaneous PSMA-avid RM1-PGLS tumors were administered18 F-PSMA-1007, and PET/CT was performed. After the animals had been killed, organs were excised and measured signals in CLI and FAR CLI were correlated with tracer activity concentrations (ACs) obtained from PET/CT. For clinical assessment, 7 high-risk PC patients underwent radical prostatectomy immediately after preoperative18 F-PSMA PET/CT. Contrast-to-noise ratios (CNRs) were calculated for both imaging modalities in intact specimens and after incision above the index lesion. Results: In the heterotopic in vivo mouse model ( n = 5), CLI did not detect any lesion. FAR CLI detected a distinct signal in all mice, with a lowest AC of 7.25 kBq/mL (CNR, 5.48). After incision above the index lesion of the prostate specimen, no increased signal was observed at the cancer area in CLI. In contrast, using FAR CLI, a signal was detectable in 6 of 7 patients. The AC in the missed index lesion was 1.85 kBq/mL, resulting in a detection limit of at least 2.06 kBq/mL. Histopathology demonstrated 2 PRMs, neither of which was predicted by CLI or FAR CLI. Conclusion:18 F-PSMA FAR CLI was superior to CLI in tracer-related signal detectability. PC was could be visualized in radical prostatectomy down to 2.06 kBq/mL. However, the detection of PRMs was limited. Direct anatomic correlation of FAR CLI is challenging because of the scintillator overlay., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
- Full Text
- View/download PDF
47. PSMA-Directed Imaging and Therapy of Salivary Gland Tumors: A Single-Center Retrospective Study.
- Author
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Civan C, Kasper S, Berliner C, Fragoso-Costa P, Grünwald V, Pogorzelski M, Schaarschmidt BM, Lang S, Kersting D, Nader M, Lückerath K, Herrmann K, Fendler WP, and Weber M
- Subjects
- Humans, Male, Female, Retrospective Studies, Gallium Radioisotopes, Dipeptides therapeutic use, Prostate-Specific Antigen, Positron Emission Tomography Computed Tomography methods, Salivary Gland Neoplasms diagnostic imaging, Salivary Gland Neoplasms radiotherapy
- Abstract
We analyzed the diagnostic performance of prostate-specific membrane antigen (PSMA) PET/CT and the dosimetry, efficacy, and safety of
177 Lu-PSMA-617 radioligand therapy (RLT) in salivary gland malignancies (SGMs). Methods: We identified 28 SGM patients with PSMA PET/CT from our database. CT and PSMA PET/CT images were evaluated separately by 3 masked readers in joint reading sessions. Pathologic findings were grouped into 6 TNM regions, and lesion-based disease extent was classified as no disease ( n = 1, 4%), unifocal ( n = 2, 7%), oligometastatic ( n = 9, 32%), multifocal ( n = 3, 11%), or disseminated ( n = 13, 47%). For each region, the SUVmax of the lesion with the highest uptake was measured and the visual PSMA expression score was evaluated on a per-patient basis using PROMISE criteria. The association between PSMA expression and clinical and histopathologic markers was tested using the Student t test. Five patients underwent PSMA RLT with intratherapeutic dosimetry. Response was assessed using RECIST 1.1, and adverse events were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events. Results: Compared with CT, PSMA PET/CT demonstrated additional metastatic lesions in 11 of 28 (39%) patients, leading to upstaging of TNM and lesion-based disease extent in 3 (11%) and 6 (21%) patients, respectively. PSMA PET/CT detected CT-occult local tumor, regional lymph nodes, nonregional lymph nodes, and bone metastases in 1 (4%), 4 (14%), 2 (7%), and 4 (14%) patients, respectively; no additional lesions were detected in the other predefined regions. PSMA expression level was higher than liver in 6 patients (25%). A significantly higher SUVmax was observed in male than female patients (15.8 vs. 8.5, P = 0.007) and in bone than lung lesions (14.2 vs. 6.4, P = 0.006). PSMA RLT was discontinued after 1 cycle in 3 of 5 patients because of insufficient tumor doses. No adverse events of grade 4 or higher occurred. Conclusion: In SGMs, PSMA PET/CT demonstrated a superior detection rate and led to upstaging in about one third of patients when compared with CT. The male sex and the presence of bone metastases were associated with significantly higher PSMA expression. PSMA RLT was well tolerated, but most patients did not have more than 1 cycle because of insufficient tumor doses., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
- Full Text
- View/download PDF
48. Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer.
- Author
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Stuparu AD, Capri JR, Meyer CAL, Le TM, Evans-Axelsson SL, Current K, Lennox M, Mona CE, Fendler WP, Calais J, Eiber M, Dahlbom M, Czernin J, Radu CG, Lückerath K, and Slavik R
- Subjects
- Humans, Male, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant
- Abstract
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA RLT. Methods: Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53
-/- tumor-bearing nonobese diabetic scid γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. Results: PSMA RLT significantly improved disease control in a dose-dependent manner. Proteome and phosphoproteome datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3-kinase/AKT, and MYC signaling. C4-2 TP53-/- tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusion: We identified signaling alterations that may mediate resistance to PSMA RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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- View/download PDF
49. PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.
- Author
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Veach DR, Storey CM, Lückerath K, Braun K, von Bodman C, Lamminmäki U, Kalidindi T, Strand SE, Strand J, Altai M, Damoiseaux R, Zanzonico P, Benabdallah N, Pankov D, Scher HI, Scardino P, Larson SM, Lilja H, McDevitt MR, Thorek DLJ, and Ulmert D
- Subjects
- Animals, Disease Models, Animal, Linear Energy Transfer, Macaca fascicularis, Male, Mice, Mice, Inbred BALB C, Positron-Emission Tomography, Prostate-Specific Antigen metabolism, Receptors, Androgen physiology, Tissue Distribution, Alpha Particles therapeutic use, Beta Particles therapeutic use, Electrons therapeutic use, Prostate-Specific Antigen immunology, Prostatic Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA ( KLK3 )., Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3 _Hi- Myc transgenic mice were imaged with
89 Zr- or treated with90 Y- or225 Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225 Ac]hu5A10 and [90 Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89 Zr]hu5A10 in nonhuman primates (NHP) were determined using PET., Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90 Y]/[225 Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( P ≤ 0.0054). Effects of [90 Y]hu5A10 were more immediate than [225 Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225 Ac]hu5A10 and 1 of 9 mice [90 Y]hu5A10. Pharmacokinetics of [89 Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89 Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period., Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer., (©2021 American Association for Cancer Research.)- Published
- 2021
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- View/download PDF
50. Immune-Checkpoint Blockade Enhances 225 Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer.
- Author
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Czernin J, Current K, Mona CE, Nyiranshuti L, Hikmat F, Radu CG, and Lückerath K
- Subjects
- Actinium, Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Male, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor immunology, Prostate-Specific Antigen, Prostatic Neoplasms pathology, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Immune Checkpoint Inhibitors pharmacology, Immunotherapy methods, Prostatic Neoplasms immunology, Prostatic Neoplasms radiotherapy
- Abstract
Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (RNT) may increase tumor immunogenicity. We aimed at exploiting this effect by combining RNT with immunotherapy in a mouse model of prostate cancer (PC). Methods: C57BL/6-mice bearing syngeneic RM1-PGLS tumors were treated with
225 Ac-PSMA617, an anti-PD-1 antibody, or both. Therapeutic efficacy was assessed by tumor volume measurements (CT), time to progression (TTP), and survival. Results: PSMA RNT or anti-PD-1 alone tended to prolong TTP (isotype control, 25 d; anti-PD-1, 33.5 d [ P = 0.0153]; RNT, 30 d [ P = 0.1038]) and survival (control, 28 d; anti-PD-1, 37 d [ P = 0.0098]; RNT, 32 d [ P = 0.1018]). Combining PSMA RNT and anti-PD-1 significantly improved disease control compared with either monotherapy. TTP was extended to 47.5 d ( P ≤ 0.0199 vs. monotherapies), and survival to 51.5 d ( P ≤ 0.0251 vs. monotherapies). Conclusion: PSMA RNT and PD-1 blockade synergistically improve therapeutic outcomes in our PC model, supporting the evaluation of RNT and immunotherapy combinations for PC patients., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
- Full Text
- View/download PDF
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