Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Positron emission tomography (PET) examinations with F-18-fluorodeoxyglucose (FDG) provide detailed information about the glucose-like metabolism in tissue. It is generally accepted that FDG reflects the viability of tumour cells. The kinetics of FDG is modulated by several genes, besides the glucose transporters and hexokinases. Additional specific information can be obtained non-invasively by using other tracers specific for cell membrane receptors. PET studies with radiolabelled peptides have emerged as a new diagnostic tool for imaging of certain tumour entities, like neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). This application is based on certain properties of these tumours, like the overexpression of somatostatin receptors, which can be visualised by somatostatin analogues, like 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic-acid-D: -Phe1-Tyr3 octreotide (DOTATOC) in NET. The overexpression of gastrin-releasing peptide (GRP) receptors can be visualised in GIST by using bombesin analogues. These peptides can be labelled by (68)Ga, which is a generator product and therefore more cost-effective than cyclotron products. (68)Ga-DOTATOC is a peptide that binds primarily to somatostatin receptor subtype 2 (SSTR2). PET studies with (68)Ga-DOTATOC are performed in patients with NET and some other tumours. (68)Ga-BZH3 ((68)Ga-Bombesin) is a peptide that binds to at least three bombesin receptor subtypes: the BB1 (also known as neuromedin B), the BB2 (also known as GRP), and the BB3 (bombesin receptor subtype 3). This bombesin analogue, (68)Ga-BZH3, is used in patients with GIST.
Methods Mol Biol 2009
PMID:Positron emission tomography (PET) and macromolecular delivery in vivo. 1908 22

The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin-dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.
J Mol Endocrinol 2009 May
PMID:The clinical-molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology. 1914 3

Molecular targeted cancer therapy (MTCT) is the "personalized" or "individualized" approaches toward cancer which targets the particular molecular or genetic changes, i.e. over-expression of molecules, and genetic amplification, mutations and translocations. MTCT is generally composed of two mechanisms, (1) humanized monoclonal antibodies (hMAB) and (2) tyrosine kinase inhibitors (TKI). Somatostatin analogue (SA) is the unique situation for the therapy of neuroendocrine tumors (NETs) which possess somatostatin receptor (SSTR). The cancers which are benefited by MTCT have been increased and will be increased to cover wide varieties of cancers. Good examples are (1) trastuzumab, hMAB against HER2 in breast cancers with HER2 over-expression and amplification, (2) imatinib, TKI, for gastrointestinal stromal tumors (GISTs) with c-kit mutation, (3) gefitinib, TKI, for lung adenocarcinoma with EGFR mutation. The drug effects have been reported to be associated with these molecular and genetic changes. It should be particularly emphasized to treat the patients with corresponding targeted molecular changes. These molecular and genetic analysis should be performed! On the right areas of the cancers, ample amount of viable cancer cells, where the major roles of pathologists are lied. This introductory review of MTCT describes more details of each MTCT.
J Cell Mol Med
PMID:Roles of pathologists in molecular targeted cancer therapy. 1989 8

Somatostatin analogs that activate the somatostatin subtype 2A (sst2A) receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable of activating multiple somatostatin receptor subtypes have been developed to increase tumor responsiveness. We tested two such multi-somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells, somatostatin inhibited cAMP production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells; pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin's actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.
Mol Endocrinol 2010 Jan
PMID:Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways. 1991 Apr 53

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.
Eur J Nucl Med Mol Imaging 2010 May
PMID:Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues. 1991 42

Pasireotide (SOM230) is currently under clinical evaluation as a successor compound to octreotide for the treatment of acromegaly, Cushing's disease, and carcinoid tumors. Whereas octreotide acts primarily via the sst(2A) somatostatin receptor, pasireotide was designed to exhibit octreotide-like sst(2A) activity combined with enhanced binding to other somatostatin receptor subtypes. In the present study, we used phophosite-specific antibodies to examine agonist-induced phosphorylation of the rat sst(2A) receptor. We show that somatostatin and octreotide stimulate the complete phosphorylation of a cluster of four threonine residues within the cytoplasmic (353)TTETQRT(359) motif in a variety of cultured cell lines in vitro as well as in intact animals in vivo. This phosphorylation was mediated by G protein-coupled receptor kinases (GRK) 2 and 3 and followed by rapid cointernalization of the receptor and ss-arrestin into the same endocytic vesicles. In contrast, pasireotide failed to promote substantial phosphorylation and internalization of the rat sst(2A) receptor. In the presence of octreotide or SS-14, SOM230 showed partial agonist behavior, inhibiting phosphorylation, and internalization of sst(2A). Upon overexpression of GRK2 or GRK3, pasireotide stimulated selective phosphorylation of Thr356 and Thr359 but not of Thr353 or Thr354 within the (353)TTETQRT(359) motif. Pasireotide-mediated phosphorylation led to the formation of relatively unstable beta-arrestin-sst(2A) complexes that dissociated at or near the plasma membrane. Thus, octreotide and pasireotide are equally active in inducing classical G protein-dependent signaling via the sst(2A) somatostatin receptor. Yet, we find that they promote strikingly different patterns of sst(2A) receptor phosphorylation and, hence, stimulate functionally distinct pools of beta-arrestin.
Mol Endocrinol 2010 Feb
PMID:Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation. 2005 80

GH promotes longitudinal growth and regulates multiple cellular functions in humans and animals. GH signals by binding to GH receptor (GHR) to activate the tyrosine kinase, Janus kinase 2 (JAK2), and downstream pathways including signal transducer and activator of transcription 5 (STAT5), thereby regulating expression of genes including IGF-I. GH exerts effects both directly and via IGF-I, which signals by activating the IGF-I receptor (IGF-IR). IGF-IR is a cell surface receptor that contains intrinsic tyrosine kinase activity within its intracellular domain. In this study, we examined the potential role of IGF-IR in facilitating GH-induced signal transduction, using mouse primary calvarial osteoblasts with Lox-P sites flanking both IGF-IR alleles. These cells respond to both GH and IGF-I and in vitro infection with an adenovirus that drives expression of Cre recombinase (Ad-Cre) dramatically reduces IGF-IR abundance without affecting the abundance of GHR, JAK2, STAT5, or ERK. Notably, infection with Ad-Cre, but not a control adenovirus, markedly inhibited acute GH-induced STAT5 activity (more than doubling the ED(50) and reducing the maximum activity by nearly 50%), while sparing GH-induced ERK activity, and markedly inhibited GH-induced transactivation of a STAT5-dependent luciferase reporter. The effect of Ad-Cre on GH signaling was specific, as platelet-derived growth factor-induced signaling was unaffected by Ad-Cre-mediated reduction of IGF-IR. Ad-Cre-mediated inhibition of GH signaling was reversed by adenoviral reexpression of IGF-IR, but not by infection with an adenovirus that drives expression of a hemagglutination-tagged somatostatin receptor, which drives expression of the unrelated somatostatin receptor, and Ad-Cre infection of nonfloxed osteoblasts did not affect GH signaling. Notably, infection with an adenovirus encoding a C-terminally truncated IGF-IR that lacks the tyrosine kinase domain partially rescued both acute GH-induced STAT5 activity and GH-induced IGF-I gene expression in cells in which endogenous IGF-IR was reduced. These data, in concert with our earlier findings that GH induces a GHR-JAK2-IGF-IR complex, suggest a novel function for IGF-IR. In addition to its role as a key IGF-I signal transducer, this receptor may directly facilitate acute GH signaling. The implications of these findings are discussed.
Mol Endocrinol 2010 Mar
PMID:Deletion of IGF-I receptor (IGF-IR) in primary osteoblasts reduces GH-induced STAT5 signaling. 2013 48

Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered limits their use in the clinical practice. This overview summarizes the state of art of NETs imaging, focusing the attention mainly on gamma-emitting tracers.
Q J Nucl Med Mol Imaging 2010 Feb
PMID:Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals. 2016 82

Neuroendocrine tumours (NET) diagnosis has represented a major challenge in the past decades. The introduction of somatostatin receptor scintigraphy in the diagnostic work-up led to a significant improvement of accuracy. However with the advent of positron emission tomography (PET) that presents a higher spatial resolution as compared to the gamma camera and an array of different radiotracers, it is now possible to image NET with an even higher accuracy. In fact, PET imaging of NET is a rapidly evolving field closely connected to the development of novel beta-emitting radiopharmaceuticals. NET can be easily visualized on PET scans using an array of both metabolic and receptor-based tracers. [18F]DOPA and [68Ga]DOTA-peptides (DOTA-TOC, DOTA-NOC, DOTA-TATE) are very promising to image well differentiated NET and were reported to be superior to other imaging modalities (computed tomography [CT], somatostatin receptor scintigraphy). On the contrary, the role of [18F]FDG is limited in well differentiated NET, due to their low glucose metabolism and growth rate, while it still can provide valuable information in less differentiated tumours. On-going studies are investigating the potential role of new imaging agents (bombesin, GLP-1, CCK) that specifically bind to receptors expressed on NET cells.
Q J Nucl Med Mol Imaging 2010 Feb
PMID:Imaging of NETs with PET radiopharmaceuticals. 2016 83

Peptide Receptor Radionuclide Therapy (PRRT) has proven its efficacy in the treatment of neuroendocrine and other somatostatin receptor expressing tumours (SR-tumours). Several clinical trials have confirmed that adverse effects are represented by possible renal impairment, which is the major concern, and low but not absent hematological toxicity. High kidney irradiation is a constant, despite the sparing of dose obtained by renal protectors. Hematological toxicity, although low, needs to be monitored. The clinical and dosimetry results collected in more than a decade have recognized weak points to unravel, increased knowledge, offering new views. When planning therapy with radiopeptides, the large patients' variability as for biodistribution and tumour uptake must be taken into account in order to tailor the therapy, or at least to avoid foreseeable gross treatments. Reliable and personalized dosimetry is more and more requested. This paper reviews through the literature the methods to study the biokinetics, the dosimetry outcomes, some clue information and correlations obtained once applying the radiobiological models. Special focus is given on recent improvements and indications for critical organ protection that light up challenging perspectives for PRRT.
Q J Nucl Med Mol Imaging 2010 Feb
PMID:Dosimetry for treatment with radiolabelled somatostatin analogues. A review. 2016 85


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