Theranostics 2016; 6(5):650-665. doi:10.7150/thno.14479

Research Paper

Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model

Martin Ullrich1, Ralf Bergmann1, Mirko Peitzsch2, Erik F. Zenker1, Marc Cartellieri3, Michael Bachmann1,3, Monika Ehrhart-Bornstein4, Norman L. Block5, Andrew V. Schally5, Graeme Eisenhofer2,4, Stefan R. Bornstein4, Jens Pietzsch1,6, Christian G. Ziegler7,8✉

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;
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.
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.

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 [177Lu]Lu-DOTA-(Tyr3)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 [64Cu]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 [177Lu]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 [177Lu]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.

Keywords: neuroendocrine tumors, catecholamines, metanephrines, DOTATATE, PET, SPECT, optical in vivo imaging, doxorubicin.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Ullrich M, Bergmann R, Peitzsch M, Zenker EF, Cartellieri M, Bachmann M, Ehrhart-Bornstein M, Block NL, Schally AV, Eisenhofer G, Bornstein SR, Pietzsch J, Ziegler CG. Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model. Theranostics 2016; 6(5):650-665. doi:10.7150/thno.14479. Available from http://www.thno.org/v06p0650.htm