RKIP level in somatotroph adenomas important for effect of octreotide treatment

Low levels of raf kinase inhibitory protein were associated with poor clinical response to somatostatin analogs in patients with acromegaly, according to new study findings.

Researchers from Norway measured raf kinase inhibitory protein levels in pituitary somatotroph adenomas from 51 patients with active acromegaly. The researchers performed an acute somatostatin test in 46 patients and they measured insulin-like growth factor-1 in 21 patients before somatostatin analog treatment and six months after treatment.

The researchers found that adenoma raf kinase inhibitory protein levels were associated with acute and long-term octreotide responses on serum levels of IGF-1 and growth hormone, according to the study.

Findings from multiple regression analyses showed that raf kinase inhibitory protein levels were a determinant for IGF-1 reduction after six months and GH reduction in the acute test, according to the study.

“Raf kinase inhibitory protein level in somatotroph adenomas seems to be important for the clinical effect of somatostatin analog treatment,” the researchers wrote in the study. – by Katie Kalvaitis

J Clin Endocrinol Metab. 2008;93:1211-1216.

Acromegaly is a chronic disease often requiring adjunctive medical therapy after surgery. Treatment with somatostatin analogs controls GH secretion in approximately 60% of patients. The variable response to medication has been attributed to the concentration of the somatostatin receptor subtype 2 (SST2) in pituitary tumor cells, but examination of this association has yielded conflicting results. Raf kinase inhibitory protein inhibits the mitogen-activated protein kinase signaling pathway which is involved in cell proliferation and apoptosis. In addition, raf kinase inhibitory protein has also been shown to inhibit G protein-coupled receptor kinase 2 (GRK2) which prevents G protein-coupled receptor internalization and desensitization resulting in prolonged receptor signaling.

This study correlates intracellular raf kinase inhibitory protein levels in cells from GH-secreting pituitary adenomas to the patients’ responses to acute and long-term treatment with somatostatin analogs. Lower levels of raf kinase inhibitory protein were associated with a poorer response to acute administration of short-acting octreotide, and to treatment with long-acting octreotide but were not associated with tumor shrinkage. Even though somatostatin receptor subtype 2 levels in these tumors were a significant determinant in octreotide response, there was no difference in raf kinase inhibitory protein levels between the different somatostatin receptor subtype 2 expression levels.

This observational study describes a potential new marker for postsurgical prediction of response to octreotide treatment. The presented correlation does not demonstrate whether raf kinase inhibitory protein has a mechanistic role in modulating octreotide-induced inhibition of GH secretion from pituitary adenomas, nor are the findings able to be generalized to somatostatin or other non-octreotide analogs. Associations are drawn to somatostatin receptor subtype 2, but no correlations are made to the other somatostatin receptor subtypes. This study raises many questions regarding the role of raf kinase inhibitory protein in somatostatin signaling and the treatment of acromegaly and more research is needed to address these important questions.

– John D. Carmichael, MD

Assistant Professor of Medicine, Cedars-Sinai Medical Center,
David Geffen School of Medicine at UCLA