Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [(177)Lu]Lu-DOTA-(Tyr(3))octreotate (DOTATATE) and AN-238.
Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [(64)Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [(177)Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [(177)Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome.
Theranostics. 2016 Mar 10*** epublish ***
Martin Ullrich, Ralf Bergmann, Mirko Peitzsch, Erik F Zenker, Marc Cartellieri, Michael Bachmann, Monika Ehrhart-Bornstein, Norman L Block, Andrew V Schally, Graeme Eisenhofer, Stefan R Bornstein, Jens Pietzsch, Christian G Ziegler
1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;, 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;, 2. Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany;, 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;, 3. University Cancer Center, Tumorimmunology, Technische Universität Dresden, Dresden, Germany;, 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;; 3. University Cancer Center, Tumorimmunology, Technische Universität Dresden, Dresden, Germany;, 4. Dept. of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany., 5. VA Medical Center Miami FL and Dept. of Pathology and Medicine, Div. of Endocrinology and Hematology-Oncology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami FL, USA., 5. VA Medical Center Miami FL and Dept. of Pathology and Medicine, Div. of Endocrinology and Hematology-Oncology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami FL, USA., 2. Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany;; 4. Dept. of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany., 4. Dept. of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany., 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;; 6. Dept. of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany;, 7. Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and faculty of Medicine, Technische Universität Dresden, Dresden, Germany;; 8. German Center for Diabetes Research e.V., Neuherberg, Germany.