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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.

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

Theranostics 6, 650-665 (2016)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dotatate ; Pet ; Spect ; Catecholamines ; Doxorubicin. ; Metanephrines ; Neuroendocrine Tumors ; Optical In Vivo Imaging; Hormone-releasing Hormone; Radionuclide Therapy; Analog An-238; Cell-lines; Peptide Analogs; In-vivo; Malignant Pheochromocytoma; Neuroendocrine Tumors; Cytotoxic Analogs; Paragangliomas
e-ISSN 1838-7640
Zeitschrift Theranostics
Quellenangaben Band: 6, Heft: 5, Seiten: 650-665 Artikelnummer: , Supplement: ,
Verlag Ivyspring
Verlagsort Lake Haven
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)