title: Multimodal Somatostatin Receptor Theranostics Using [(64)Cu]Cu-/[(177)Lu]Lu-DOTA-(Tyr(3))octreotate and AN-238 in a Mouse Pheochromocytoma Model.
abstract: 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.
authors.affiliation: 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Ullrich
authors.affiliation: 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: 2. Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany;
authors.forename: Mirko
authors.initials: M
authors.lastname: Peitzsch
authors.affiliation: 1. Dept. of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;
authors.forename: Erik F
authors.initials: EF
authors.lastname: Zenker
authors.affiliation: 3. University Cancer Center, Tumorimmunology, Technische Universität Dresden, Dresden, Germany;
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.affiliation: 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;
authors.forename: Michael
authors.initials: M
authors.lastname: Bachmann
authors.affiliation: 4. Dept. of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.affiliation: 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.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: 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.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: 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.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: 4. Dept. of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: 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;
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: 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.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Ziegler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D015282:Octreotide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010456:Peptides, Cyclic; D010673:Pheochromocytoma / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D017481:Receptors, Somatostatin / Q000378:metabolism; D000068936:Theranostic Nanomedicine / Q000379:methods*; D016896:Treatment Outcome
chemical_list: C504257:177Lu-octreotide, DOTA(0)-Tyr(3)-; C110845:AN 238; D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D011758:Pyrroles; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-; D004317:Doxorubicin; D015282:Octreotide
keywords: DOTATATE; PET; SPECT; catecholamines; doxorubicin.; metanephrines; neuroendocrine tumors; optical in vivo imaging