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Endocrine Abstracts (2015) 37 GP17.09 | DOI: 10.1530/endoabs.37.GP.17.09

1Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, CIBER Fisiopatolo, University of Cordoba, Córdoba, Spain; 2Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, University of Cordoba, Córdoba, Spain; 3Service of Endocrinology and Nutrition, Hospital Universitario Reina Sofia, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain; 4Service of Neurosurgery, Hospital Universitario Reina Sofia, Córdoba, Spain; 5Metabolism and Nutrition Unit, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla, Spain; 6Department of Morphological Sciences, University of Cordoba, Córdoba, Spain; 7Endocrinology and Nutrition Unit, Complejo Hospitalario de Jaén, Jaén, Spain; 8Service of Endocrinology and Nutrition, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain; 9Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 10Department of Endocrinology and Nutrition, Carlos Haya Hospital, Málaga, Spain; 11Department of Endocrinology, Centre for Biomedical Research on Rare Diseases (Centro de Investigación Biomédica en Red de Enfermedades Raras Unit 747), Hospital Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; 12Research and Development Division, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, University of Illinois at Chicago, Chicago, Illinois, USA; 13IPSEN Bioscience, Cambridge, Massachusetts, USA.


Chimeric somatostatin (SST)/dopamine (DA) compounds, termed dopastatins, such as BIM-23A760, an agonist for SST (sst2 and ss5) and DA (D2) receptors, are emerging as promising new approaches to treat pituitary adenomas. However, their actions and mechanisms on the different types of pituitary tumours are still incompletely understood. Thus, the aim of this study was to analyse a set of key functional parameters (signaling pathways, hormonal expression and secretion, cell viability, and apoptosis), in response to BIM-23A760 in a series of 74 human pituitary tumors: 22 somatotropinomas, five mixed GH/PRL-secreting adenomas, 11 corticotropinomas, 26 NFPAs, six prolactinomas, one FSH-secreting gonadotropinoma and three TSH-omas; and in five normal human pituitaries and pituitary samples derived from three female olive baboons (Papio anubis). Although, BIM-23A760 has recently been withdrawn from clinical development after finding that a dopaminergic metabolite accumulates and interferes with the activity of the parent compound in vivo, it is still considered a good prototype molecule for dopastatins, and the results generated herein might be indeed useful in understanding and predicting the response to this type of compounds, which may be used for clinical purposes in the future. Our results demonstrate that BIM-23A760 differentially impacted all functional parameters analysed, with most responses being clearly inhibitory for cell signalling, hormone secretion and cell survival. Yet, interestingly, certain pituitary adenomas displayed distinct, even opposite responses to BIM-23A760 (i.e. paradoxical stimulatory responses), which were associated with the relative expression levels of SST- and DA-receptors. In particular, alterations on the expression of sst5 and its truncated variant, sst5TMD4, might represent potential molecular signatures contributing to the differential, inhibitory/stimulatory response to BIM-23A760 in GH- and ACTH-secreting adenomas. Altogether, our results reinforce the notion that chimeric dopastatins (e.g. BIM-23A760) can affect multiple, clinically relevant parameters on most types of pituitary adenomas and may represent new therapeutic tools to treat pituitary tumours, wherein the relative SST/DA receptor expression profile might provide useful molecular markers to predict the ultimate response of these tumours to BIM-23A760.

Disclosure: This work was supported by Junta de Andalucía (CTS-1406, BIO-0139, PI-0639-2012) Ministerio de Economía y Competitividad, Gobierno de España (BFU2013-43282-R), Instituto de Salud Carlos III (PI13/00651), Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Ayuda Merck Serono 2013. M D Culler is an employee of IPSEN.

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