Multimodal Somatostatin Receptor Theranostics Using [(64)Cu]Cu-/[(177)Lu]Lu-DOTA-(Tyr(3))octreotate and AN-238 in a Mouse Pheochromocytoma Model

Theranostics. 2016 Mar 10;6(5):650-65. doi: 10.7150/thno.14479. eCollection 2016.

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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