Endocrinol Metab.  2020 Mar;35(1):177-187. 10.3803/EnM.2020.35.1.177.

Therapeutic Effect of a Novel Chimeric Molecule Targeting Both Somatostatin and Dopamine Receptors on Growth Hormone-Secreting Pituitary Adenomas

• Kim J
• Oh JH
• Harlem H
• Culler MD
• Ku CR
• Lee EJ

• KMID: 2471734
• DOI: http://doi.org/10.3803/EnM.2020.35.1.177

Abstract

BACKGROUND
Acromegaly is a rare disease primarily caused by growth hormone (GH)-secreting pituitary adenomas, and its treatment is costly. Moreover, some patients are unresponsive to treatment. Hence, there are increasing efforts to develop new drugs with improved effectiveness for this disease. BIM23B065 is a novel chimeric molecule that acts on both somatostatin and dopamine receptors. This study aimed to investigate the effects of BIM23B065 compared with those of a somatostatin receptor analog and a dopamine agonist.
METHODS
The effects of BIM23B065 on the proliferation, GH and insulin-like growth factor-1 (IGF-1) levels, and extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element binding (CREB) phosphorylation of GH3 cells were investigated with MTS assay, enzyme-linked immunosorbent assay, and Western blotting, respectively. The dosage and treatment duration of BIM23B065 were tested in animal models of GH-secreting pituitary adenoma. The effect of BIM23B065 (3 mg/kg/day) on changes in IGF-1 levels before and after treatment was further investigated.
RESULTS
In vitro, BIM23B065 treatment decreased GH release in the culture media and downregulated ERK 1/2 and CREB phosphorylation to 22% and 26%, respectively. In vivo, IGF-1 expression decreased to 50 % after 4 weeks of treatment with BIM23B065 using an osmotic pump implant. Moreover, magnetic resonance imaging results showed that the tumor size decreased significantly following treatment with BIM23B065 for 4 weeks.
CONCLUSION
The novel chimeric molecule was effective in decreasing IGF-1 and GH levels and may serve as an effective therapeutic agent for acromegaly.

Keyword

Acromegaly; Therapeutics; Growth hormone; Insulin-like growth factor I; Pituitary neoplasms

MeSH Terms

Acromegaly
Blotting, Western
Culture Media
Cyclic AMP
Dopamine Agonists
Dopamine*
Enzyme-Linked Immunosorbent Assay
Growth Hormone
Growth Hormone-Secreting Pituitary Adenoma*
Humans
In Vitro Techniques
Insulin-Like Growth Factor I
Magnetic Resonance Imaging
Models, Animal
Phosphorylation
Phosphotransferases
Pituitary Neoplasms
Rare Diseases
Receptors, Dopamine*
Receptors, Somatostatin
Response Elements
Somatostatin*
Culture Media
Cyclic AMP
Dopamine
Dopamine Agonists
Growth Hormone
Insulin-Like Growth Factor I
Phosphotransferases
Receptors, Dopamine
Receptors, Somatostatin
Somatostatin

Figure

• 

  Fig. 1 Effects of lanreotide, cabergoline, and BIM23B065 on growth hormone 3 (GH3) cells. (A) Cell proliferation assay. (B) Change in growth hormone release in the medium after 48 hours of treatment. (C) Changes in phospho-cyclic AMP response element binding (p-CREB) and phospho-extracellular signal-regulated kinase (p-ERK) 1/2 after 15 minutes of drug treatment. DMSO, dimethyl sulfoxide; LAN, lanreotide; CAB, cabergoline. aP<0.05.

• 

  Fig. 2 Seven-day treatment of BIM23B065 at different concentrations. (A) Insulin-like growth factor-1 (IGF-1) level change in each group after BIM23B065 treatment. (B) Weight change before and after BIM23B065 treatment and (C) daily blood glucose levels during treatment.

• 

  Fig. 3 Effects of lanreotide, cabergoline, and BIM23B065 after 4-week treatment in somatotroph-specific aryl hydrocarbon receptor interacting protein knockout (sAIPKO) mice. (A) Change in insulin-like growth factor-1 (IGF-1) level after 4-week treatment with lanreotide and BIM23B065. (B) Average weight change before and after treatment. (C) Change in blood glucose level throughout the treatment duration. aP<0.001.

• 

  Fig. 4 Effects of BIM23B065 on tumor size and pituitary gland size in somatotroph-specific aryl hydrocarbon receptor interacting protein knockout (sAIPKO) mice. (A) Changes in average tumor volume after 4-week treatment. (B) Changes in average pituitary gland size after treatment and (C) magnetic resonance images before and after treatment showing decrease in tumor size in axial and sagittal views (white bar: 2 mm).

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