Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists.

Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-Gi complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gαi protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor.

Structural insights into ligand recognition and selectivity of somatostatin receptors.

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism.

SST5 receptor activation potently inhibits insulin secretion from pancreatic ß-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors. Leading compound 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl-5-fluorobenzonitrile (28, CRN02481) showed limited off-target activity and good pharmacokinetic profiles in both male Sprague Dawley rats and Beagle dogs to advance into further preclinical evaluations.

Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand-binding specificity.

Somatostatin is a peptide hormone that regulates endocrine systems by binding to G-protein-coupled somatostatin receptors. Somatostatin receptor 2 (SSTR2) is a human somatostatin receptor and is highly implicated in hormone disorders, cancers, and neurological diseases. Here, we report the high-resolution cryo-EM structure of full-length human SSTR2 bound to the agonist somatostatin (SST-14) in complex with inhibitory G (Gi) proteins. Our structural and mutagenesis analyses show that seven transmembrane helices form a deep pocket for ligand binding and that SSTR2 recognizes the highly conserved Trp-Lys motif of SST-14 at the bottom of the pocket. Furthermore, our sequence analysis combined with AlphaFold modeled structures of other SSTR isoforms provide a structural basis for the mechanism by which SSTR family proteins specifically interact with their cognate ligands. This work provides the first glimpse into the molecular recognition mechanism of somatostatin receptors and a crucial resource to develop therapeutics targeting somatostatin receptors.

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations.

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.

Design, synthesis, and biological evaluation of novel somatostatin receptor subtype-2 agonists: Optimization for potency and risk mitigation of hERG and phospholipidosis.

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.

Clinical and Radiological Predictors of Biochemical Response to First-Line Treatment With Somatostatin Receptor Ligands in Acromegaly: A Real-Life Perspective.

Background: First-generation somatostatin receptor ligands (fg-SRLs) represent the first-line medical treatment for acromegaly, recommended in patients with persistent disease after neurosurgery, or when surgical approach is not feasible. Despite the lack of strong recommendations from guidelines and consensus statements, data from national Registries report an increasing use of medical therapy as first-line treatment in acromegaly. Objective: We retrospectively evaluated the potential role of a large number of clinical and radiological parameters in predicting the biochemical response to 6-month treatment with fg-SRLs, in a cohort of naïve acromegaly patients referred to a single tertiary center for pituitary diseases. Methods: Univariable and multivariable logistic regression and linear regression analyses were performed. Biochemical response was defined based on IGF-1 levels, represented as both categorical (tight control, control, >50% reduction) and continuous (linear % reduction) variables. Results: Fifty-one patients (33 females, median age 57 years) were included in the study. At univariable logistic regression analysis, we found that younger age (≤ 40 years; OR 0.04, p=0.045) and higher BMI (OR 0.866, p=0.034) were associated with a lower chance of achieving >50% IGF-1 reduction. On the contrary, higher IGF-1 xULN values at diagnosis (OR 2.304, p=0.007) and a T2-hypointense tumor (OR 18, p=0.017) were associated with a significantly higher likelihood of achieving >50% IGF-1 reduction after SRL therapy. Of note, dichotomized age, IGF1 xULN at diagnosis, and T2-hypointense signal of the tumor were retained as significant predictors by our multivariable logistic regression model. Furthermore, investigating the presence of predictors to the linear % IGF-1 reduction, we found a negative association with younger age (≤ 40 years; ß -0.533, p<0.0001), while a positive association was observed with both IGF-1 xULN levels at diagnosis (ß 0.330, p=0.018) and the presence of a T2-hypointense pituitary tumor (ß 0.466, p=0.019). All these variables were still significant predictors at multivariable analysis. Conclusions: Dichotomized age, IGF-1 levels at diagnosis, and tumor T2-weighted signal are reliable predictors of both >50% IGF-1 reduction and linear % IGF-1 reduction after 6 month fg-SRL treatment in naïve acromegaly patients. These parameters should be considered in the light of an individualized treatment for acromegaly patients.

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons.

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

Neuroprotective effect of the somatostatin receptor 5 agonist L-817,818 on retinal ganglion cells in experimental glaucoma.

Somatostatin plays important roles in modulating neuronal functions by activating the five specific G-protein coupled receptors (sst1-sst5). Previous studies have demonstrated that sst5 were expressed in retinal ganglion cells (RGCs) and sst5 agonist attenuated the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-induced retinal neurotoxicity. In this study, we investigated effects and underlying mechanisms of the sst5 agonist L-817,818 on RGC injury induced by elevated intraocular pressure (COH) in experimental glaucoma. Our results showed that intraperitoneal administration of L-817,818 significantly reduced RGC loss and decreased the number of terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL)-positive RGCs in COH retinas, suggesting that L-817,818 may attenuate RGC apoptosis. Consistently, in COH retinas with L-817,818 administration, both the down-regulated mRNA and protein levels of anti-apoptotic Bcl-2 and the up-regulated mRNA and protein levels of pro-apoptotic Bax were partially reversed. L-817,818 administration downregulated the expression of apoptosis-related proteins caspase-9 and caspase-3 in COH retinas. In addition, L-817,818 administration reduced the concentrations of reactive oxygen species/reactive nitrogen species and malondialdehyde, and ameliorated the functions of mitochondrial respiratory chain complex (MRCC). Our results imply that administration of the sst5 agonist L-817,818 reduces RGC loss in COH rats through decreasing RGC apoptosis, which is mediated by regulating Bcl-2/Bax balance, reducing oxidative stress and rescuing activities of MRCC. Activation of sst5 may provide neuroprotective roles for RGCs in glaucoma.

The role of somatostatin and its receptors (sstr2, sstr5) in the contractility of gilt inflamed uterus.

We studied the inflammation effect on somatostatin receptors subtypes 2 (sstr2) and 5 (sstr5) expression in myometrium and somatostatin influence alone or with sstr2 and sstr5 antagonists on the contractility of gilt inflamed uterus. On day 3 of the estrous cycle, either E.coli suspension (E.coli group) or saline (SAL group) were injected into uterine horns. In the control pigs (CON group), only laparotomy was performed. Eight days later, in the E.coli group developed severe acute endometritis. In this group, myometrial sstr2 mRNA expression lowered and protein expression increased compared to other groups. Compared to period before somatostatin administration, somatostatin did not change tension in myometrium and endometrium/myometrium of three groups, reduced amplitude and frequency in the CON and SAL groups, and increased amplitude and decreased frequency in the E.coli group. In this group, amplitude was increased by somatostatin compared to other groups. In the CON and SAL groups, sstr2 eliminated inhibitory somatostatin effect on amplitude, while sstr5 antagonist reversed inhibitory somatostatin effect on amplitude. In the E.coli group, sstr2 antagonist reversed stimulatory somatostatin effect on amplitude, while in sstr5 antagonist presence stimulatory somatostatin effect was more deepened compared to somatostatin action alone. After using sstr2 antagonist more deepened inhibitory somatostatin effect on frequency in the CON and E.coli groups was found. Sstr5 antagonist partly eliminated inhibitory somatostatin effect on frequency in the SAL group. Summarizing, the uterine inflammation increases the myometrial sstr2 protein expression; somatostatin raises amplitude of the inflamed uterus acting by sstr2, while drops this parameter by sstr5.

Distance-Dependent Cellular Uptake of Oligoproline-Based Homobivalent Ligands Targeting GPCRs-An Experimental and Computational Analysis.

Tumor targeting with bivalent radiolabeled ligands for GPCRs is an attractive means for cancer imaging and therapy. Here, we studied and compared the distance dependence of homobivalent ligands for the human gastrin-releasing peptide receptor (hGRP-R) and the somatostatin receptor subtype II (hSstR2a). Oligoprolines were utilized as molecular scaffolds to enable distances of 10, 20, or 30 Å between two identical, agonistic recognition motifs. In vitro internalization assays revealed that ligands with a distance of 20 Å between the recognition motifs exhibit the highest cellular uptake in both ligand series. Structural modeling and molecular dynamics simulations support an optimal distance of 20 Å for accommodating ligand binding to both binding sites of a GPCR dimer. Translation of these findings to the significantly higher complexity in vivo proved difficult and showed only for the hGRP-R increased tumor uptake of the bivalent ligand.

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains.

Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates.

Fluorescent Nanoparticles Coated with a Somatostatin Analogue Target Blood Monocyte for Efficient Leukaemia Treatment.

BACKGROUND: Leukaemia is the most prevalent form of cancer-causing death in a large number of populations and needs prompt and effective treatment. Chemotherapeutics can be used to treat leukaemia, but their pronounced killing effects to other living cells is still an issue. Active targeting to certain specific receptors in leukaemic cells is the best way to avoid damage to other living cells. Leukaemic cells can be targeted using novel nanoparticles (NPs) coated with a specific ligand, such as octreotide (OCD), to target somatostatin receptor type 2 (SSTR2), which is expressed in leukaemic cells. METHODS: Amino-PEGylated quantum dots (QDs) were chosen as model NPs. The QDs were first succinylated using succinic anhydride and then coated with OCD. The reactivity and selectivity of the formulated QDs-OCD were studied in cell lines with well-expressed SSTR2, while fluorescence was detected using confocal laser scanning microscopy (CLSM) and flow cytometry (FACS). Conclusively, QD-OCD targeting to blood cells was studied in vivo in mice and detected using inductively coupled plasma mass spectrometry and CLSM in tissues. RESULTS: Highly stable QDs coated with OCD were prepared. FACS and CLSM showed highly definite interactions with overexpressed SSTR2 in the investigated cell lines. Moreover, the in vivo results revealed a higher concentration of QDs-OCD in blood cells. The fluorescence intensity of the QDs-OCD was highly accumulated in blood cells, while the unmodified QDs did not accumulate significantly in blood cells. CONCLUSION: The formulated novel QDs-OCD can target SSTR2 overexpressed in blood cells with great potential for treating blood cancer.

Cost-Effectiveness and Efficacy of a Novel Combination Regimen in Acromegaly: A Prospective, Randomized Trial.

CONTEXT: Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied. OBJECTIVE: To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly. DESIGN AND SETTING: Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center. PATIENTS: Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment. INTERVENTION: Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day). MAIN OUTCOME MEASURE: Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy. RESULTS: Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ±â€…1375 per month), arm C was most expensive (mean, $22543 ±â€…11158 per month), and arm A had an intermediate cost (mean, $14261 ±â€…1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%. CONCLUSIONS: Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.

Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel.

Small molecule somatostatin receptor subtype 4 (sst4) agonists are novel anti-inflammatory and analgesic drug candidates.

We provided strong proof of concept evidence that somatostatin mediates potent analgesic and anti-inflammatory actions via its receptor subtype 4 (sst4) located both at the periphery and the central nervous system. Therefore, sst4 agonists are promising novel drug candidates for neuropathic pain and neurogenic inflammation, but rational drug design was not possible due to the lack of knowledge about its 3-dimensional structure. We modeled the sst4 receptor structure, described its agonist binding properties, and characterized the binding of our novel small molecule sst4 agonists (4-phenetylamino-7H-pyrrolo[2,3-d]pyrimidine derivatives) using an in silico platform. In addition to the in silico binding data, somatostatin displacement by Compound 1 was demonstrated in the competitive binding assay on sst4-expressing cells. In vivo effects were investigated in rat models of neurogenic inflammation and chronic traumatic neuropathic pain. We defined high- and low-affinity binding pockets of sst4 for our ligands, binding of the highest affinity compounds were similar to that of the reference ligand J-2156. We showed potent G-protein activation with the highest potency of 10 nM EC50 value and highest efficacy of 342%. Oral administration of 100 µg/kg of 5 compounds significantly inhibited acute neurogenic plasma protein extravasation in the paw skin by 40-60%, one candidate abolished and 3 others diminished sciatic nerve-ligation induced neuropathic hyperalgesia by 28-62%. The in silico predictions on sst4-ligands were tested in biological systems. Low oral dose of our novel agonists inhibit neurogenic inflammation and neuropathic pain, which opens promising drug developmental perspectives for these unmet medical need conditions.

Patient reported outcome data from acromegaly patients treated with injectable somatostatin receptor ligands (SRLs) in routine clinical practice.

BACKGROUND: Acromegaly patients managed on Somatostatin receptor ligands (SRLs), the most common first-line pharmacotherapy for acromegaly, may still experience acromegaly symptoms such as headache, sweating, fatigue, soft tissue swelling, and joint pain, even those with normal IGF-1. Additionally, treatment with SRLs may cause injection site reactions and other side effects such as gastro-intestinal (GI) symptoms. This study utilized patient-reported outcome measures to examine the burden associated with acromegaly and its treatment for patients receiving a stable dose of long-acting SRLs in routine clinical practice. METHODS: US acromegaly patients on a stable dose of SRL seen by their treating healthcare provider in the past 12 months completed a one-time online survey including the Acro-TSQ, an acromegaly-specific tool for assessing symptom burden and treatment satisfaction and convenience. RESULTS: One hundred five patients were enrolled (mean age 49.9 years, 79.1% female). Patients experienced numerous symptoms, including > 80% who experienced joint pain, acro-fog, swelling of soft tissue, and fatigue/weakness. Many symptoms occurred constantly, while some occurred at the end of the injection cycle, even among those with IGF-1 < = 1.0 ULN. Injection site reactions were common. Patients were moderately satisfied with their current treatment; symptoms and side effects often affected daily activities. On average, patients reported > 3 acromegaly provider visits/year. CONCLUSIONS: Despite receiving a stable dose of SRL and regular visits with an acromegaly healthcare provider, US acromegaly patients in routine clinical practice, and even the subgroup with normal IGF-1, report significant burden of disease and treatment.

Normal Insulin-like Growth Factor 1 During Somatostatin Receptor Ligand Treatment Predicts Surgical Cure in Acromegaly.

CONTEXT: Treatment with somatostatin receptor ligands (SRLs) is often given before pituitary surgery to patients with acromegaly. OBJECTIVE: To study whether the response to treatment with SRLs is predictive of surgical outcome. DESIGN: Retrospective, observational study. SETTING: Tertiary care center. PATIENTS: We investigated 272 patients with acromegaly who had been treated with an SRL between 1990 and 2018. INTERVENTION: All patients underwent pituitary surgery performed by a skilled neurosurgeon. MAIN OUTCOME MEASURE: Outcome of pituitary surgery in patients who had normalization of insulin-like growth factor 1 (IGF-1) levels during SRL therapy in comparison with patients who did not normalize IGF-1 levels. RESULTS: Normalization of IGF-1 levels during SRL treatment occurred in 62 patients (22.8%) and was similar for the 3 different types of SRL (P = .88). Surgical remission occurred in 59.6% of the patients. Patients who normalized IGF-1 levels during SRL treatment had a higher probability of surgical cure than patients without IGF-1 normalization (83.9% vs 52.4%, respectively; P < .001). Multivariate analysis confirmed that lack of cavernous sinus invasion, small maximum tumor diameter, and IGF-1 normalization during SRL therapy were the only factors independently associated with a favorable surgical outcome. CONCLUSIONS: Our study demonstrates that the normalization of IGF-1 levels during treatment with SRLs is an independent predictive factor of a favorable surgical outcome. The underlying mechanisms remain unclear, but an optimal response to medical therapy may be a characteristic of less aggressive tumors that are more likely to be entirely removed at surgery.

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

CONTEXT: First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. OBJECTIVE: To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. DESIGN: Retrospective multicenter study. SETTING: Eight participating European centers. METHODS: We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. RESULTS: Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (ß = 0.90, standard error (SE) = 0.02, P ≤ .0001 and ß â€…= 0.002, SE = 0.001, P = .014, respectively). CONCLUSION: Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Somatostatin receptor expression and patients' response to targeted medical treatment in pituitary tumors: evidences and controversies.

BACKGROUND: Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST2 and SST5 are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST2, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST5 and SST2. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors. METHODS: Critical revision of literature data correlating SST expression with patients' response to SRLs. RESULTS: SST2 expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST2 immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST2 in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST2 expression, pasireotide can act throughout SST5. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST2 expression observed in nearly 100% of cases, as well as to the balanced amount of SST5. In corticotroph tumors, pasireotide mainly act via SST5, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype. CONCLUSIONS: The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.