Effect of a novel somatostatin receptor 5/3 agonist, HTL0030310, on human GH- and ACTH-secreting pituitary adenomas in vitro  

D. Regazzo*^a (Dr), S. Avallone^b (Mrs), C. Macsweeney^c (Dr), E. Sergeev^c (Dr), D. Howe^c (Dr), A. Godwood^c (Dr), G. Occhi^d (Prof), M. Barbot^e (Dr), D. Faggian^f (Mr), M. Losa^g (Prof), G. Lasio^h (Dr), C. Scaroni^e (Prof), F. Pecori Giraldiⁱ (Prof)

^a Dip Medicina, Università di Padova, Padova, ITALY ; ^b Dip Medicina, Università di Padova; Dip DISCLIMO, Università Politecnica delle Marche, Padova-Ancona, ITALY ; ^c Sosei Heptares, Cambridge, UNITED KINGDOM ; ^d Dip Biologia, Università degli studi di Padova, Padova, ITALY ; ^e UO Endocrinologia, Dip di Medicina, Ospedale-Università di Padova, Padova, ITALY ; ^f UO Medicina di Laboratorio, Dip di Medicina, Ospedale-Università di Padova, Padova, ITALY ; ^g Dip Neurochirurgia, IRCCS Ospedale San Raffaele, Milano, ITALY ; ^h Dip Neurochirurgia, IRCCS Istituto Clinico Humanitas, Rozzano, ITALY ; ⁱ Dip. Scienze Cliniche & di Comunità, University di Milano, Milano, ITALY

* daniela.regazzo@unipd.it

Somatostatin agonists have come to play a pivotal role in the treatment of both GH-secreting and ACTH-secreting pituitary adenomas. Clinical efficacy averages 50% in patients with acromegaly (Gadelha 2022) and 30% in patients with Cushing’s disease (Pivonello 2020), thus a considerable number of patients remain as yet unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin agonist selective for receptor subtypes 5 and 3 (Congreve 2022), unlike the clinical somatostatin agonists which also act at subtype 2. The aim of the present study was to evaluate the effect of HTL0030310, on hormone secretion in human GH-secreting and ACTH-secreting pituitary adenomas in vitro.

Methods: Eight GH-secreting and 3 ACTH-secreting pituitary adenomas were collected during surgery and established in culture as per our protocol (Pecori Giraldi 2011). Specimens were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM GHRH or CRH, respectively. GH and ACTH medium concentrations were measured by Elisa after 4 and 24-hour incubation.

Results: HTL0030310 proved capable of reducing hormone secretion in pituitary adenomas. In detail, a marked reduction in spontaneous GH secretion was observed in 5 specimens and in 3 out of 5 specimens co-incubated with GHRH. Among ACTH-secreting adenomas, spontaneous ACTH secretion was reduced up to 50% of baseline in 2 specimens whereas a decrease in CRH-stimulated ACTH secretion was observed in all 3 specimens.

Conclusions: Our findings indicate that this somatostatin receptor 5/3 agonist can inhibit hormonal secretion in human GH- and ACTH-secreting pituitary adenomas and suggest a potential new avenue for somatostatin analogs in the treatment of acromegaly and Cushing’s disease

References:

Congreve (2022) SST5 agonist peptide HTL0030310 using structure-based drug design AACS Spring Meeting

Gadelha (2022) The future of somatostatin receptor ligands in acromegaly J Clin Endocrinol Metab 107: 297-308.

Pivonello (2020) Medical treatment of Cushing's disease: overview of current and recent clinical trials. Front Endocrinol 11:648.

Pecori Giraldi (2011) Responses to corticotrophin-releasing hormone and dexamethasone in a large series of human adrenocorticotropic hormone-secreting pituitary adenomas in vitro reveal manifold corticotroph tumoural phenotypes. J Neuroendocrinol 23:1214-21.

This study was sponsored by Sosei Heptares, Cambridge (UK)

The author has declared the following conflict(s) of interest:

This study was sponsored by Sosei Heptares, Cambridge (UK).