Current therapy and drug pipeline for the treatment of patients with acromegaly.
BACKGROUND
Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy.


RESULTS
Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated.


CONCLUSIONS
Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management.
Kumar
Sampath Satish
SS
Department of Endocrinology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, UK.
Ayuk
John
J
Murray
Robert D
RD
D000172:Acromegaly / Q000188:drug therapy* / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism; D000236:Adenoma / Q000150:complications; D003131:Combined Modality Therapy; D004298:Dopamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000627:therapeutic use; D055808:Drug Discovery; D004341:Drug Evaluation; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000150:complications; D011878:Radiotherapy / Q000379:methods / Q000639:trends; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
D018491:Dopamine Agonists; D018970:Insulin-Like Growth Factor Binding Protein 1; D017448:Receptors, Dopamine D2; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D013004:Somatostatin; C517782:pasireotide; C531242:TBR-760; C406545:pegvisomant; D004298:Dopamine