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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)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
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
Journal
Theranostics
Quellenangaben
Volume: 6,
Issue: 5,
Pages: 650-665
Publisher
Ivyspring
Publishing Place
Lake Haven
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute for Pancreatic Beta Cell Research (IPI)