Evolving concepts in the quest for advanced therapeutic analogues of somatostatin

A major challenge in developing somatostatin-based therapies, as well as an important question of basic physiology, is how to achieve functional specificity with an agent that has widespread actions. The natural somatostatin system achieves functional specificity in part through local somatostatin production at the site of action. Further selectivity may be achieved through the recently elucidated somatostatin receptor subtypes. To explore the relationship between the receptor subtypes and somatostatin-mediated functions, we have tested panels of selective somatostatin analogs in specific biological assays. Our studies have demonstrated complex, functional interactions between the somatostatin receptor subtypes. Specific combinations of somatostatin receptor subtypes in specific tissues may be either synergistic or antagonistic. By altering the expression ratio of the interacting receptors, the biological response to somatostatin can be influenced by environmental, hormonal and physiological status. In addition, inappropriate or unbalanced receptor expression may provide a novel mechanism of disease. These concepts take on an even broader context with the demonstration that somatostatin receptor subtypes also interact with other G-protein-coupled receptors. The insight gained from these studies has already resulted in several novel approaches to acromegaly therapy. Our further understanding of these complex cellular codes will provide the conceptual basis for future therapeutics with greatly enhanced efficacy and specificity.