Dopastatin: an evolving story
Somatostatin receptors (sstr15) and dopamine receptor 2 (D2DR) are expressed and co-localized in several endocrine tumors including pituitary adenomas that express both D2DR and various subtypes of somatostatin receptors, depending on the original cell type. Treatment of pituitary adenomas using somatostatin or dopamine analogs targets only one receptor (octreotide/lanreotide mainly sst2, cabergoline D2DR). Association of octreotide and cabergoline showed limited additive effects in GH adenomas both in vivo and in vitro. Sst5 agonists showed in vitro the capacity to suppress hormonal secretion in pituitary adenomas, and pasireotide, targeting both sst5 and sst2, showed efficacy in controlling GH and ACTH hypersecretion.
Both sst2 and sst5 are able to form heterodimers with D2DR, which modifies ligand binding and signal transduction in a cooperative manner. Sst2-D2DR cooperation may be more efficiently triggered through so-called dopastatins i.e. hybrid dopamine and somatostatin agonists. In GH tumoral cells in vitro, characterized by a balanced sst2/D2DR expression, dopastatins showed a synergic effect on cell secretion and proliferation by acting through both sst2 and D2DR receptors. In vivo phase IIA single dose study of BIM-23A760 dopastatin showed encouraging efficacy and safety profile. However, in a phase IIb repeat dosing clinical trial, a strong dopaminergic activity was observed, but little evidence of somatostatinergic activity with weak inhibition of both GH and IGF1. In other types of pituitary adenomas presenting lower sst2 expression, dopastatin showed in vitro an antisecretory and antiproliferative effects similar to D2DR agonists. In prolactinomas resistant to D2DR agonist treatment, sst2 overexpression induced a sst2/D2DR balance similar to that of GH adenomas. However inhibition of PRL secretion induced by dopastatin remained similar to that obtained by the reference D2DR agonist.
Gastro-entero pancreatic neuroendocrine tumors (GEPNET) and other neuroendocrine tumors, like pheochromocytomas and paragangliomas, express both sstr and D2DR, opening the way for potential sst2D2DR cooperation in these tumors. Further studies are underway to validate the interest of chimeric agonists in pituitary adenomas and other neuroendocrine tumors.
Declaration of interest: The author declares that there is a conflict of interest.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.