Illuminating somatostatin analog action at neuroendocrine tumor receptors

Abstract

Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These advances increased understanding of the biological role of each somatostatin receptor subtype, their distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and phosphorylation, particularly for the sst2 receptor subtype, which is the primary target of current somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the development of tumor resistance to therapy. In addition, we now have a better understanding of the action of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDA-approved somatostatin analogs, including the biased agonistic character of some agonists. The increased understanding of somatostatin receptor pharmacology provides new opportunities to design more sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.

Keywords: lanreotide; octreotide; pasireotide; sst receptors.

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Phosphorylation of the sst2A receptor

Panel A. Diagram of the potential and demonstrated phosphorylation sites in the sst2A receptor. The structure depicts the carboxy-terminal portion of the rat sst2A receptor. Identified phosphorylation sites are colored orange or torquoise whereas potential, but not yet identified, phosphorylation sites are shown in grey. The rat and human sst2A receptors differ only by the two residues shown in purple (AE in rsst2A ->TD in hsst2A). Somatostatin stimulates the GRK-catalyzed phosphorylation of all orange and torquoise Ser and Thr residues whereas protein kinase C activation only stimulates the phosphorylation of the sites shown in orange. (Modified from ). Panel B Octreotide treatment of patients stimulates sst2A phosphorylation in NETs. Immunohistochemistry was carried out with either an sst2A antibody that is insensitive to receptor phosphorylation (UMB-1) (Left panels) or an antibody specific for pSer341/343 (Ra-1124) (Right Panels). The top panels show immunohistochemistry of a NET from an octreotide-treated patient and identifies phosphorylated, internalized receptors. The lower panels show immunohistochemistry of a NET from an untreated patient and identifies unphosphorylated, cell surface receptors. (Bars = 0.1 mm) . Panel C Agonist specific phosphorylation of the sst2A receptor. CHO cells expressing the rat sst2A receptor were incubated at 37°C for 30 min with varying concentrations of either somatostatin (left panel) or KE108 (right panel). Receptor phosphorylation was measured at steady state using phospho-site-specific monoclonal antibodies with an ELISA. Somatostatin stimulates the phosphorylation at both sets of phosphosites with similar potency (Left panel). KE108 is both less efficacious at stimulating receptor phosphorylation than somatostatin and, in addition, stimulates phosphorylation at pSer341-343 more potently than at pT353-354. (Adapted from108108).