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Joost van der Hoek The functional role of in pituitary adenomas somatostatin receptor subtypes The functional role of somatostatin receptor subtypes in pituitary adenomas J. van der Hoek The functional role of somatostatin receptor subtypes in pituitary adenomas Cover Design: Frans Bukkens ISBN-10: 90-9020597-7 ISBN-13: 978-90-9020597-7 Niets uit deze uitgave mag worden verveelvoudigd en/of openbaar gemaakt worden zonder voorafgaande schriftelijke toestemming van de auteur. No part of this thesis may be reproduced in any form without permission from the author. © 2006 J. van der Hoek Printed by HAVEKA BV, Alblasserdam, The Netherlands THE FUNCTIONAL ROLE OF SOMATOSTATIN RECEPTOR SUBTYPES IN PITUITARY ADENOMAS DE FUNCTIONELE BETEKENIS VAN SOMATOSTATINE RECEPTOR SUBTYPEN IN HYPOFYSE ADENOMEN Proefschrift ter verkrijging van de graag van doctor aan de Erasmus Universiteit Rotterdam Op gezag van de rector magnifi cus Prof. dr. S.W.J. Lamberts en volgens besluit van het College voor Promoties De openbare verdediging zal plaatsvinden op woensdag 17 mei 2006 om 15.45 uur door Johannes van der Hoek geboren te Dordrecht Promotiecommissie Promotor: Prof.dr. S.W.J. Lamberts Overige leden: Prof.dr. A.H.J. Danser Prof.dr. A.J. van der Lelij Prof.dr.ir. T.J. Visser Copromotor: Dr. L.J. Hofl and Paranimfen: Marlijn Waaijers Christiaan de Bruin Dit proefschrift is tot stand gekomen binnen de afdeling Inwendige Geneeskunde van het Erasmus MC Rotterdam. De druk van dit proefschrift is fi nancieel mogelijk gemaakt door Novartis Oncology en IPSEN Pharmaceutica BV. voor Duifi e, Tim en Naud Contents Chapter I 9 INTRODUCTION Chapter II 37 AIM OF THE THESIS Chapter III 43 CLINICAL POTENTIAL OF SOM230 IN THE MEDICAL TREATMENT OF ACROMEGALY Chapter III-1 45 The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone and prolactin secreting pituitary adenomas in vitro Chapter III-2 69 A single dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients Chapter III-3 91 The somatostatin analog SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients Chapter III-4 113 Somatostatin receptors in peripheral target tissues of insulin action: implications for glucose homeostasis during somatostatin analog treatment? Chapter IV 131 FUNCTIONAL CHARACTERISATION OF SOMATOSTATIN RECEPTOR SUBTYPES 2 AND 5 Chapter IV-1 133 Functional interplay between somatostatin receptor subtype 2 and 5 when variably co-expressed in vitro Chapter IV-2 161 RNA interference as a novel tool to study somatostatin receptor function Chapter V 175 SOMATOSTATIN RECEPTOR SUBTYPE 5 IN CUSHING’S DISEASE; IN VITRO SUPPORT FOR NOVEL THERAPEUTIC OPPORTUNITIES Chapter V-1 177 The multiligand somatostatin analog SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor subtype 5 Chapter V-2 201 Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by cultured mouse corticotroph tumour cells Chapter VI 229 THE ROLE OF NOVEL SOMATOSTATIN ANALOGS IN THE TREATMENT OF NEUROENDOCRINE TUMOURS Chapter VI-1 231 Novel subtype specifi c and universal somatostatin analogues: Clinical potential and pitfalls Chapter VI-2 267 Tachyphylaxis of somatostatin receptors is differentially regulated by somatostatin analogs Chapter VI-3 289 Functional characterisation of the novel tri-selective chimeric molecule BIM-23A760 with activity at somatostatin receptors 2 and 5, and the dopamine D2 receptor Chapter VII 307 GENERAL DISCUSSION Chapter VIII 327 SUMMARY-SAMENVATTING Dankwoord 341 List of publications & Curriculum Vitae 349 Chapter I INTRODUCTION Adapted from: Pituitary. 2004;7(4):257-64 The Endocrinologist. 2005;15 (6): 377-383 General Introduction Somatostatin and somatostatin receptors Over three decades have now elapsed since Brazeau and Guillemin origi- nally detected a somatotropin release-inhibiting factor (SRIF) by chance during studies of the distribution of growth hormone-releasing factor in the hypothalamus of rats (1). This peptide, called somatostatin because of its supposed specifi c function, i.e. the inhibition of somatotropin [growth hormone (GH)] release, proved to be a cyclic peptide consisting out of 14 amino acids (Fig. 1). Higher molecular weights forms of SRIF immunoreactivity have been reported including a 28-amino acid Lys Asn Phe Phe Ala Gly Cys Trp Cys LysLys SRIF-14 Ser Thr Phe Thr Figure 1. Amino acid sequence of the natural somatostatin peptide SRIF-14. polypeptide that corresponds to SRIF with a NH2-terminal extension of 14 amino acids. Isolation and characterization of complementary DNA (cDNA) clones encoding SRIF indicated that SRIF, like other polypep- tides, is derived from a larger precursor by proteolytic processing. The primary translation product of SRIF messenger RNA (mRNA) is a 116- amino acid molecule, preprosomatostatin, subsequently processed in a 92-amino acid prosomatostatin which by itself undergoes proteolytic processing, thereby generating the biologically active forms SRIF-14 and SRIF-28. The production of SRIF occurs in concentrated numbers of SRIF-producing cells throughout the central and peripheral nervous systems, in the endocrine pancreas, in the gut and in limited cell numbers distributed over the thyroid, the retina, adrenals, submandibular glands, kidneys, prostate and placenta. SRIF modulates neurotransmission in the central nervous system (as a neurotransmitter), regulates the release of GH and thyrotropin (TSH) from the anterior pituitary gland (as a neuro- hormone) and has a regulatory role in the gastrointestinal tract, as well as in the exocrine and endocrine pancreas. When synthesized in and re- 11 Chapter I leased by endocrine and nerve cells, SRIF acts in an autocrine, paracrine, or neuronal regulatory manner to inhibit glandular secretion, neurotransmission, smooth muscle contractility and absorption of nutrients (2, 3). Somatostatin receptor subtypes The various actions of SRIF are mediated through specifi c membrane receptors. Five subtypes of the human SRIF receptor (sst) have been cloned and characterized (4, 5). Genes for sst1,3,4,5 lack classical introns. The sst2 gene displays a cryptic intron at the 3’ end of the coding seg- ment, which gives rise to two splice variants, a long (sst2A) form and a shorter (sst2B) form, which differ only in the length of their cytoplasmic tail (6, 7). Even though Northern blotting has detected two bands of 2.3 kb and 8.0 kb size-length in human tissues (6, 8, 9), detailed evidence for the (functional) expression of the short sst2B form in humans is still lacking. The sst subtypes, which are identical in 42 to 60 percent of their amino acid sequences, belong to a superfamily of seven α helical transmembrane segments typical of guanine nucleotide binding (G) protein coupled receptors (GPCR; Fig. 2). All subtypes share a coupling to the Figure 2. Structure and schematic orientation of the SRIF receptor within the plasma membrane encountering seven transmembrane-spanning α-helical domains connected by short loops, having an N-terminal extracellular domain and a C-terminal intracellular domain. second messenger system known to be activated upon SRIF binding to its receptors. Hydrophobic and charged amino acids within transmembrane domains 3, 6 and 7 are important for the interaction with the ligand 12 General Introduction (10, 11). However, the extracellular loop 2, between domains 4 and 5 may also be involved (12-14). The subsequent conformational change of the receptor leads to activation of an associated heterotrimeric G-protein complex (consisting of α-, β- and γ-subunits) and exchange of GTP for GDP on the α-subunit. The common effect of the fi ve sst subtypes is a reduction in intracellular cyclic adenosine monophosphate (cAMP) and Ca++ as well as an activation of protein phosphatases [Fig. 3; (15)]. The fi nal pathway, and hence effect on cellular function, will vary, depending on the specifi c sst and SRIF ligand involved. Inhibition of cell secretion may be achieved through several intracellular effector pathways: (1) inhibition of adenylyl cyclase activity via inhibitory G proteins (Gαi), which are pertussis toxin sensitive, thereby reducing intracellular cAMP levels, (2) reduction in intracellular Ca2+ owing to activation and hyper- polarisation of K+ channels as well as inhibition of the normal depolariza- tion-induced Ca++ infl ux via voltage-sensitive Ca++ channels (16). Both a reduction on intracellular cAMP and Ca++ result in inhibition of secretion. Stimulation of protein tyrosine phosphatases and inhibition of MAP ki- nase activity (17) by sst are thought to be involved in anti-proliferative effects of SRIF. Less prominent signaling pathways include inhibition of Na+-H+ exchanger and activation of phospholipase A and C (2, 18). SRIF G adenylyl cyclase protein tyrosine phosphatase � �K+/ � Ca++ channels MAPK� Ca++� cAMP � Figure 3. Schematic representation of SRIF receptor signaling pathways leading to inhibition of secretion and cell proliferation. 13 Chapter I Distribution of somatostatin receptor subtypes Classical SRIF-target tissues such as the central nervous system, the anterior pituitary gland and the pancreas, express multiple sst subtypes (Table I) (19). The adult human pituitary gland expresses sst1, sst2, sst3 and sst5 mRNAs, but not sst4 mRNA. As determined by immunohistochemistry, the human pancreatic

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