Pharmacological characterization of somatostatin receptor subtype 3 as a potential strategy to treat non-functioning pituitary adenomas

Mari C Vazquez-Borrego; Alejandro Ibanez-Costa; Manuel D Gahete; Alvaro Toledano-Delgado; Cristobal Blanco-Acevedo; Rosa Ortega-Salas; Eva Venegas-Moreno; Alexandre Vasiljevic; Maria A Galvez-Moreno; Alfonso Soto-Moreno; Gerald Raverot; Marcelo Paez-Pereda; Michael D Culler; Justo P Castano; Raul M Luque

doi:10.1530/endoabs.56.GP200

Non-functioning pituitary adenomas (NFPAs) represent the most common type of pituitary adenomas. NFPAs are mostly macroadenomas (>1 cm) at diagnosis and, despite their lack of functional hormone hypersecretion, are associated to severe comorbidities related to mass effect (i.e. headaches, visual defects and hypopituitarism). Transsphenoidal surgery is the mainstay of NFPAs treatment, although it is often not definitive, mainly due to the invasion of neighboring intracranial structures precluding complete resection. Unfortunately, there are no medical treatments currently approved or recommended to manage NFPAs. Indeed, somatostatin analogs (SSAs), commonly used to treat functioning pituitary adenomas, have been largely ineffective in NFPAs, which might be explained by the limited expression of the main targets for these SSAs, i.e. somatostatin-receptor subtypes 2 (sst2) and 5 (sst5). However, since it has been previously demonstrated that NFPAs present a predominant expression of sst3, the main objectives of this study were: 1) to perform a comprehensive characterization of the expression pattern of sst3 in NFPA and normal-pituitary (NP) tissues (by qPCR and IHC); and, 2) to determine the functional role of sst3 in NFPA by analyzing different functional endpoints (i.e. cell-viability, apoptosis, chromogranin-A secretion, mRNA expression and intracellular signaling pathways) in primary NFPA cell-cultures in response to selective sst3 agonists and antagonists. Our results demonstrate that sst3 is the most abundantly expressed sst-subtype in NFPAs (n=71), being also significantly overexpressed in NFPAs compared to NPs (n=12) and functioning pituitary adenomas like GHomas (n=63) and ACTHomas (n=17). Treatment with sst3-agonists reduced cell viability and chromogranin-A secretion, while increasing apoptotic rate in primary NFPA cell-cultures. These inhibitory effects of sst3-agonists were completely reversed by specific sst3-antagonists, confirming the specificity of the effects observed. Interestingly, our data revealed the existence of two distinct subgroups of NFPAs that responded differentially (responsive vs. unresponsive) to treatment with sst3-agonists in terms of reduction in cell viability, being sst3 expression levels higher in responsive NFPAs. Further analysis revealed that the effects of sst3-agonists might be mediated by the inhibition of MAPK-pathways, as suggested by reduced phosphorylation levels of ERK1/2 and JNK. Altogether, our study provides novel data strongly supporting that sst3 plays a relevant functional role in the pathophysiology of NFPAs, and suggests that pharmacological treatments targeting this receptor could be a promising therapeutic alternative for these tumors.

Endocrine Abstracts

GP200