Novel somatostatin analogs for treatment of Graves’ orbitopathy

TOPIC: Graves' orbitopathy

Title: Modulation of expression of somatostatin receptor subtypes in Graves' ophthalmopathy orbits: relevance to novel analogues

Authors: Cozma I, Zhang L, Uddin J, Lane C, Rees A, & Ludgate M

Reference: Am J Physiol Endocrinol Metab 293: E1630-E1635, 2007 (ahead of print)

Summary

Background

Treatment of Graves'orbitopathy (GO) with two somatostatin analogs, octreotide and lanreotide, has been attempted with disappointing results. Octreotide (OCT) and lanreotide mostly bind to somatostatin receptor (SSTR) subtypes 2 & 5. Novel somatostatin analogs with broader affinity for SSTRs might be more effective.

Purpose

The aim of the study was to investigate SSTR expression ex vivo and to evaluate the effect on preadipocyte proliferation of a novel synthetic somatostatin analog, SOM230, which has a high affinity for a wider range of SSTR subtypes (SSTR 1, 2, 3 & 5).

Methods

Orbital/adipose tissue was obtained for quantitative PCR studies from 23 GO patients (with inactive disease) and 8 individuals operated on orbital decompression for non-thyroid related ocular diseases. In cultured orbital preadipocytes obtained from 6 additional GO patients (with inactive disease), adipocyte differentiation was obtained by exposure to a peroxisome proliferator-activated receptor- (PPAR) agonist. In this system, the possible effect of TSH receptor (TSHR) activation was evaluated by introducing activating mutant or wild type TSHR into orbital preadipocytes using retroviral vectors. The effect of varying concentrations of OCT and SOM230 on preadipocyte differentiation and proliferation was assessed.

Results

The expression of SSTR 1 was significantly higher in GO orbital tissue than in control orbital tissue; the expression of SSTR 2 tended to be higher in GO patients, although this did not reach significance; SSTR 3, SSTR 4 and SSTR 5 were expressed at very low levels or were undetectable. TSHR activation did not modulate SSTR expression. In the in vitro model of adipogenesis, SSTR 1 and SSTR 2 were upregulated during adipocyte differentiation; in this system SOM230 produced a greater inhibition of orbital preadipocyte proliferation than octreotide.

Conclusions

SSTR 1 and, to a lesser extent, SSTR 2 were expressed at a higher level in orbital tissue from GO patients than from controls. Ex vivo analysis of orbital tissues revealed upregulation of SSTR 1 and SSTR 2 in GO patients during adipocyte differentiation. SOM230 reduced preadipocyte proliferation to a greater extent than octreotide.

Commentary

Treatment of GO with traditional therapies (intravenous glucocorticoids, orbital radiotherapy) is only partially effective, and patients are eventually unsatisfied with treatment outcome in about one third of the cases. Demonstration of SSTR expression in orbital fibroblasts and lymphocytes derived from GO patients prompted the use of somatostatin analogs (octreotide or lanreotide, mainly interacting with SSTR2 and, to a lesser extent, SSTR 5). After initial positive reports in small and uncontrolled studies, four randomized controlled trials (three using octreotide LAR and one using lanreotide) showed that benefit from such treatment is marginal (if any) in GO. However, it was suggested that novel somatostatin analogs with a wider affinity for SSTR should be investigated and might prove beneficial for the orbitopathy.

The present study showed a higher level of expression of SSTR 1 and, to a lower extent, SSTR 2 in orbital tissue from GO patients than from controls. This expression appeared to be unrelated to TSHR activation, thus limiting the putative role of TSHR antibodies. SSTR 1 and SSTR 2 were up-regulated during the process of differentiation of predipocyte into mature adipocytes, thus explaining their increased expression measured in GO samples ex vivo . The most interesting finding was the observation that SOM230 exerted a greater inihibitory effect on preadipocyte proliferation than octreotide.

These ex vivo and in vitro results suggest that SOM230 might be beneficial (or more beneficial than octreotide or lanreotide) for GO also in vivo . It is likely that the effects might be more favorable if treatment is administered during the early phases of the disease, when the proliferation and/or differentiation of orbital tissue is still in an active ongoing process. However, randomized controlled trials enrolling a sufficiently large number of patients are warranted to establish whether SOM230 may really represent a useful tool in the management of this invalidating disease. Summary and commentary prepared by Luigi Bartalena (related to Chapter 12 of TDM) Full paper obtainable at http://ajpendo.physiology.org/cgi/reprint/full/293/6/E1630