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: 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
• Journal: Theranostics (Theranostics) Vol. 6 Issue 5 Pg. 650-65 ( 2016) ISSN: 1838-7640 [Electronic] Australia
• PMID: 27022413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 177Lu-octreotide, DOTA(0)-Tyr(3)-
• AN 238
• Antineoplastic Agents
• Peptides, Cyclic
• Pyrroles
• Radiopharmaceuticals
• Receptors, Somatostatin
• octreotate, Tyr(3)-
• Doxorubicin
• Octreotide

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Disease Models, Animal
• Doxorubicin (administration & dosage, analogs & derivatives)
• Mice
• Octreotide (administration & dosage, analogs & derivatives)
• Peptides, Cyclic
• Pheochromocytoma (drug therapy)
• Pyrroles (administration & dosage)
• Radiopharmaceuticals (administration & dosage)
• Receptors, Somatostatin (metabolism)
• Theranostic Nanomedicine (methods)
• Treatment Outcome