Multimodal somatostatin receptor theranostics using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a mouse pheochromocytoma model

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

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamineproducing 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.

Original languageEnglish (US)
Pages (from-to)650-665
Number of pages16
JournalTheranostics
Volume6
Issue number5
DOIs
StatePublished - Mar 10 2016

Keywords

  • Catecholamines
  • DOTATATE
  • Doxorubicin
  • Metanephrines
  • Neuroendocrine tumors
  • Optical in vivo imaging
  • PET
  • SPECT

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Fingerprint Dive into the research topics of 'Multimodal somatostatin receptor theranostics using [<sup>64</sup>Cu]Cu-/[<sup>177</sup>Lu]Lu-DOTA-(Tyr<sup>3</sup>)octreotate and AN-238 in a mouse pheochromocytoma model'. Together they form a unique fingerprint.

  • Cite this

    Ullrich, M., Bergmann, R., Peitzsch, M., Zenker, E. F., Cartellieri, M., Bachmann, M., Ehrhart-Bornstein, M., Block, N. L., Schally, A. V., Eisenhofer, G., Bornstein, S. R., Pietzsch, J., & Ziegler, C. G. (2016). Multimodal somatostatin receptor theranostics using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a mouse pheochromocytoma model. Theranostics, 6(5), 650-665. https://doi.org/10.7150/thno.14479