RESUMEN
Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Desoxicitidina , Gemcitabina , Neoplasias Pancreáticas , Receptores de Somatotropina , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Ratones , Receptores de Somatotropina/metabolismo , Receptores de Somatotropina/antagonistas & inhibidores , Receptores de Somatotropina/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Ratones Desnudos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , FemeninoRESUMEN
Pegvisomant is a growth-hormone (GH) receptor antagonist that prevents the formation of the active heterotrimer of the dimerised GH receptor and the GH molecule necessary for downstream signal transduction. Over the past 20 years, it has become a key therapeutic option for physicians treating syndromes of GH/IGF-1 excess. Sufficient longitudinal follow-up data suggest that it can be deemed both safe and effective. It is the drug with the greatest potential for achieving an amelioration of the biochemical effects of GH excess with a corresponding normalisation of IGF-1 levels; however, insufficient dose titration has lessened real-world therapeutic outcomes. Theoretical concerns about stimulating tumour growth have been resolved as this has not been observed, while derangement of liver enzymes and local skin-related adverse reactions may occur in a minority of the patients. It may be a particularly impactful medication for the treatment of children, young people, and those with inherited disorders of GH excess, where other treatment modalities often fail. Combination therapy of pegvisomant with first- and second-generation somatostatin receptor ligands or with dopamine agonists remains an ongoing area of interest and research. High cost remains a barrier to the use of pegvisomant in many settings.
Asunto(s)
Hormona de Crecimiento Humana , Receptores de Somatotropina , Humanos , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/uso terapéutico , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/tratamiento farmacológicoRESUMEN
Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to the development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarize methodologies and approaches used for making and purifying recombinant GH and GHA proteins, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins. Therapeutics that are in clinical use or are currently under development are also discussed.
Asunto(s)
Hormona de Crecimiento Humana , Receptores de Somatotropina , Humanos , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/farmacología , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Receptores de Somatotropina/agonistas , Receptores de Somatotropina/antagonistas & inhibidoresRESUMEN
Excess circulating human growth hormone (hGH) in vivo is linked to metabolic and growth disorders such as cancer, diabetes, and acromegaly. Consequently, there is considerable interest in developing antagonists of hGH action. Here, we present the design, synthesis, and characterization of a 16-residue peptide (site 1-binding helix [S1H]) that inhibits hGH-mediated STAT5 phosphorylation in cultured cells. S1H was designed as a direct sequence mimetic of the site 1 mini-helix (residues 36-51) of wild-type hGH and acts by inhibiting the interaction of hGH with the human growth hormone receptor (hGHR). In vitro studies indicated that S1H is stable in human serum and can adopt an α-helix in solution. Our results also show that S1H mitigates phosphorylation of STAT5 in cells co-treated with hGH, reducing intracellular STAT5 phosphorylation levels to those observed in untreated controls. Furthermore, S1H was found to attenuate the activity of the hGHR and the human prolactin receptor, suggesting that this peptide acts as an antagonist of both lactogenic and somatotrophic hGH actions. Finally, we used alanine scanning to determine how discrete amino acids within the S1H sequence contribute to its structural organization and biological activity. We observed a strong correlation between helical propensity and inhibitory effect, indicating that S1H-mediated antagonism of the hGHR is largely dependent on the ability for S1H to adopt an α-helix. Taken together, these results show that S1H not only acts as a novel peptide-based antagonist of the hGHR but can also be applied as a chemical tool to study the molecular nature of hGH-hGHR interactions.
Asunto(s)
Péptidos/farmacología , Receptores de Somatotropina/antagonistas & inhibidores , Línea Celular , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Modelos Moleculares , Péptidos/química , Fosforilación/efectos de los fármacos , Conformación Proteica , Receptores de Somatotropina/química , Receptores de Somatotropina/metabolismo , Factor de Transcripción STAT5/metabolismoRESUMEN
The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
Asunto(s)
Acromegalia/terapia , Consenso , Agonistas de Dopamina/uso terapéutico , Procedimientos Neuroquirúrgicos , Grupo de Atención al Paciente , Guías de Práctica Clínica como Asunto , Radioterapia , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análisis , Acromegalia/diagnóstico , Humanos , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/normas , Radioterapia/métodos , Radioterapia/normasRESUMEN
OBJECTIVE: To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I). DESIGN: Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant). METHODS: Kaplan-Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk. RESULTS: The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02-1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population. CONCLUSIONS: Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.
Asunto(s)
Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Mortalidad , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/metabolismo , Adulto , Factores de Edad , Anciano , Causas de Muerte , Estudios de Cohortes , Femenino , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Tiempo de TratamientoRESUMEN
Growth hormone (GH) deficiency is associated with cognitive decline which occur both in normal aging and in endocrine disorders. Several brain areas express receptors for GH although their functional role is unclear. To determine how GH affects the capacity for learning and memory by specific actions in one of the key areas, the hippocampus, we injected recombinant adeno-associated viruses (rAAVs) in male rats to express green fluorescent protein (GFP) combined with either GH, antagonizing GH (aGH), or no hormone, in the dorsal CA1. We found that aGH disrupted memory in the Morris water maze task, and that aGH treated animals needed more training to relearn a novel goal location. In a one-trial spontaneous location recognition test, the GH treated rats had better memory performance for object locations than the two other groups. Histological examinations revealed that GH increased the dendritic spine density on apical dendrites of CA1, while aGH reduced the spine density. GH increased the relative amount of immature spines, while aGH decreased the same amount. Our results imply that GH is a neuromodulator with strong influence over hippocampal plasticity and relational memory by mechanisms involving modulation of dendritic spines. The findings are significant to the increasing aging population and GH deficiency patients.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Hormona del Crecimiento/farmacología , Hormona del Crecimiento/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Dependovirus , Hormona del Crecimiento/administración & dosificación , Masculino , Ratas , Ratas Long-Evans , Receptores de Somatotropina/antagonistas & inhibidoresRESUMEN
This post-marketing surveillance is to investigate the long-term safety and effectiveness of the growth hormone receptor antagonist pegvisomant, which is used in patients with acromegaly in routine clinical practice. This surveillance included all cases treated with pegvisomant during the study period from the start of marketing (June 5, 2007) to December 2015. Data for 251 patients with acromegaly treated with pegvisomant were collected from 119 institutions nationwide in Japan. Eighty-five patients received pegvisomant monotherapy throughout their treatment, while 165 patients were treated with somatostatin analogue or dopamine agonist in combination with pegvisomant. Mean dose of pegvisomant was 10.6 ± 6.1 mg/day in the entire treatment period (except for initial loading dose). The incidence of adverse drug reactions was 35.6% (89/250). No new safety concerns related to long-term treatment were observed. The major investigation items of incidence of abnormal liver function and tumor enlargement were 16.0% (40/250), and 5.2% (13/250) respectively. Efficacy at the final evaluation point was 96.4% (217/225) based on the overall clinical judgement of attending physicians, and efficacy in each observation period was over 94%. Improvement in IGF-I levels and clinical symptoms scores were also observed by comparing the data at baseline with each observation point during treatment. IGF-I normalization rate was 68.2% at 5 years. Pegvisomant monotherapy showed similar improvement here as well. These results suggest that long-term treatment with pegvisomant is effective in clinical practice.
Asunto(s)
Acromegalia/tratamiento farmacológico , Adenoma/terapia , Antineoplásicos Hormonales/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/etiología , Acromegalia/metabolismo , Adenoma/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bromocriptina/uso terapéutico , Cabergolina/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Niño , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Japón/epidemiología , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Octreótido/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Vigilancia de Productos Comercializados , Radioterapia , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Carga Tumoral , Adulto JovenRESUMEN
Osteosarcoma (OS) is the primary bone malignancy in children and adolescents, with a high incidence of lung metastasis and poor prognosis. Here, we report that growth hormone receptor (GHR) is overexpressed in OS samples compared with osteofibrous dysplasia. We subsequently demonstrated that GHR knockdown inhibited colony formation, promoted cell apoptosis and decreased the number of cells at G2/M phase in 143B and U2OS cells. Furthermore, knockdown of GHR inhibited tumor growth in vivo. Together, these findings indicate that GHR modulates cell proliferation and metastasis through the phosphoinositide 3-kinase/AKT signaling pathway and may be suitable for use as a putative biomarker of OS.
Asunto(s)
Enfermedades del Desarrollo Óseo/metabolismo , Neoplasias Óseas/metabolismo , Osteosarcoma/metabolismo , Receptores de Somatotropina/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Enfermedades del Desarrollo Óseo/tratamiento farmacológico , Enfermedades del Desarrollo Óseo/patología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , ARN Interferente Pequeño/farmacología , Receptores de Somatotropina/antagonistas & inhibidores , Receptores de Somatotropina/genética , Células Tumorales CultivadasRESUMEN
CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.
Asunto(s)
Acromegalia/sangre , Proteína Relacionada con Agouti/sangre , Antagonistas de Hormonas/uso terapéutico , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/tratamiento farmacológico , Acromegalia/cirugía , Adenoma/sangre , Adenoma/tratamiento farmacológico , Adenoma/cirugía , Adulto , Femenino , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Neoplasias Hipofisarias/sangre , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Pegvisomant (PEG) in monotherapy or combined with somatostatin analogs (SSAs) is used to control acromegaly, improving metabolism. However, the metabolic changes induced by PEG have not been systematically reviewed. OBJECTIVE: To address the following questions: does PEG or the combination of PEG and SSAs affect fasting plasma glucose (FPG), glycosylated Hb (HbA1c), glucose load (2-hour oral glucose tolerance test), insulin levels [fasting plasma insulin (FPI)], homeostatic model assessment of insulin resistance (HOMA-I), homeostatic model assessment of ß-cell function, lipid profile, or body mass index? Are the effects disease-related or drug-related? DATA SOURCES: Indexed databases up to January 2019. STUDY SELECTION: Prospective interventional trials reporting glycometabolic outcomes under PEG or PEG plus SSAs for a minimum of 6 months. DATA EXTRACTION: Three reviewers screened eligible publications (7248), three others extracted the outcomes, and all assessed the risk of biases. DATA SYNTHESIS: Thirteen studies were included in the PEG and 5 in the PEG plus SSAs analysis (overall 550 subjects). PEG significantly decreased FPG [effect size (ES) -0.80 mmol/L (95% CI, -1.06 to -0.55); P = 0.000], HbA1c [ES -0.43% (95% CI, -0.56 to -0.31); P = 0.000], FPI [ES -5.31 mU/L (95% CI, -10.23 to -0.39); P = 0.034], and HOMA-I [ES -0.61 (95% CI, -1.17 to -0.04); P = 0.034]. Effects on FPG and FPI were not correlated to IGF-1 changes. The addition of PEG to SSAs mitigated the effects of SSAs on metabolism, producing an overall neutral effect. CONCLUSIONS: Independently of disease control, PEG in monotherapy or combined with SSAs seems to improve glucose metabolism, reducing FPG, HbA1c, FPI, and HOMA-I.
Asunto(s)
Acromegalia/tratamiento farmacológico , Hormona de Crecimiento Humana/análogos & derivados , Somatostatina/análogos & derivados , Acromegalia/metabolismo , Glucemia/metabolismo , Índice de Masa Corporal , Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Quimioterapia Combinada , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Resistencia a la Insulina , Octreótido/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/uso terapéutico , Triglicéridos/metabolismoRESUMEN
CONTEXT: Pegvisomant, a growth hormone receptor (GHR) antagonist, is a well-known drug that was designed to treat acromegaly. However, recent studies have indicated that the GHR is a "moonlighting" protein that may exhibit dual functions based on its localization in the plasma membrane and nucleus. In light of this finding, we explored whether pegvisomant is a potential "moonlighting" GHR antagonist. In addition, the mechanisms of the endocytosis, postendocytic sorting, and degradation of pegvisomant are not fully understood. OBJECTIVE: This study investigated whether pegvisomant is a "moonlighting" antagonist and explored the mechanisms of the endocytosis, postendocytic sorting, and degradation of pegvisomant. METHODS: Indirect immunofluorescence and Western blot coupled with pharmacological inhibitors and gene silencing (small interfering RNA) were used to explore the mechanisms of the endocytosis, postendocytic sorting, and degradation of pegvisomant. Western blot, immunohistochemistry, and indirect immunofluorescence coupled with subcellular fractionation analysis were used to determine the effect of pegvisomant on GHR's nuclear localization in vitro and in vivo. RESULTS: Here, we show that the endocytosis of pegvisomant is mainly mediated though the clathrin pathway. Further study of the postendocytic sorting of pegvisomant shows that pegvisomant enters into different types of endosomes under GHR mediation. In addition, GHR is slightly downregulated by pegvisomant; further study indicates that proteasomes and lysosomes may cooperate to regulate pegvisomant/GHR degradation. Most importantly, we show that pegvisomant inhibits the nuclear localization of GHR. CONCLUSION: Our study showed that pegvisomant is a "moonlighting" antagonist. In addition, we revealed the mechanisms of the endocytosis, postendocytic sorting, and degradation of pegvisomant.
Asunto(s)
Núcleo Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatotropina/antagonistas & inhibidores , Acromegalia/tratamiento farmacológico , Animales , Células CHO , Caveolinas/antagonistas & inhibidores , Caveolinas/genética , Caveolinas/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Clatrina/antagonistas & inhibidores , Clatrina/genética , Clatrina/metabolismo , Cricetulus , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/metabolismo , Antagonistas de Hormonas/uso terapéutico , Hormona de Crecimiento Humana/farmacología , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Ratones , Modelos Animales , ARN Interferente Pequeño/metabolismo , Receptores de Somatotropina/metabolismo , Proteínas Recombinantes/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52.
Asunto(s)
Agonistas de Dopamina/administración & dosificación , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatostatina/administración & dosificación , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análogos & derivados , Acromegalia/tratamiento farmacológico , Quimioterapia Combinada , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Calidad de Vida , Somatostatina/administración & dosificaciónRESUMEN
OBJECTIVE: The aim of this study was to compare antioxidant vitamin C and vitamin E levels in the non-acromegaly control group and in patients with acromegaly with and without remission. MATERIAL AND METHODS: In this study, 100 cases, acromegaly patients of 57% (n=57, 29F, 28M, mean ages of 49.5±12.1) and control subjects of 43% (n=43, 29F, 14M, mean ages of 49.6±9.2). Acromegaly patients were classified into two groups; active acromegaly (AA; n=33) and controlled acromegaly (CA; n=24). RESULTS: Vitamin C levels were significantly lower in the acromegaly group [7.6 (4.7) mg/L, as median (IQR)] when compared to the control group [12.2 (5.5) mg/L, as median (IQR)] (p <0.001). Vitamin E levels didn't show a significant difference between the acromegaly and the control groups (14.2±3.6 vs. 14.8±3.7, as mean±SD, respectively, p = 0.439). Correlation analysis showed that vitamin C levels were not significantly associated with clinical, anthropometric and laboratory parameters in the acromegaly group. Vitamin E levels were significantly associated with the total cholesterol, triglyceride, LDL-C, HDL-C, APO A1, APO B both in the acromegaly and the control groups. CONCLUSION: This study is the first one to investigate the relationship between the levels of vitamin C & E and anthropometric & metabolic parameters in acromegaly patients and control group. In our study, vitamin C level was significantly lower in the acromegaly group compared to the level in the control group. There was no significant difference in vitamin E levels between the acromegaly and control group.
Asunto(s)
Acromegalia/sangre , Ácido Ascórbico/sangre , Vitamina E/sangre , Acromegalia/tratamiento farmacológico , Tejido Adiposo , Adulto , Apolipoproteína A-I/sangre , Apolipoproteínas B/sangre , Composición Corporal , Índice de Masa Corporal , Estudios de Casos y Controles , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Impedancia Eléctrica , Femenino , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Resistencia a la Insulina , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Somatotropina/antagonistas & inhibidores , Triglicéridos/sangre , Circunferencia de la CinturaRESUMEN
BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta-analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00-0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment.
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Acromegalia/tratamiento farmacológico , Antagonistas de Hormonas/uso terapéutico , Hormona de Crecimiento Humana/análogos & derivados , Hormona de Crecimiento Humana/metabolismo , Péptidos Cíclicos/uso terapéutico , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análogos & derivados , Acromegalia/metabolismo , Acromegalia/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Antagonistas de Hormonas/efectos adversos , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/efectos adversos , Receptores de Somatotropina/metabolismo , Somatostatina/efectos adversos , Somatostatina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The growth hormone (GH) plays a key role in the regulation of metabolic processes in an organism. Determination of the correct structure and functioning of the growth hormone receptor (GHR) allowed for a more detailed research of its post-receptor regulators, which substantially influences its signal transduction. This review is focused on the description of the post-receptor inhibitors of the GHR-JAK2-STAT pathway, which is one of the most important pathways in the transduction of the somatotropic axis signal. The aim of this review is the short characterization of the main post-receptor inhibitors, such as: cytokine-inducible SH2-containing protein (CIS), Suppressors of Cytokine Signaling (SOCS) 1, 2 and 3, sirtuin 1 (SIRT1), protein inhibitors of activated STAT (PIAS) 1, 3 and PIAS4, protein tyrosine phosphatases (PTP) 1B and H1, Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP) 1, 2 and signal regulatory protein (SIRP) α1. The equilibrium between these regulators activity and inhibition is of special concern because, as many studies showed, even slight imbalance may disrupt the GH activity causing serious diseases. The regulation of the described inhibitors expression and activity may be a point of interest for pharmaceutical industry.
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Hormona del Crecimiento/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Receptores de Somatotropina/antagonistas & inhibidores , Factores de Transcripción STAT/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Janus Quinasa 2/metabolismo , Modelos Biológicos , Receptores de Somatotropina/metabolismo , Factores de Transcripción STAT/metabolismoRESUMEN
OBJECTIVE: ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. DESIGN: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. METHODS: The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. RESULTS AND CONCLUSIONS: Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.
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Oligonucleótidos Antisentido , Oligonucleótidos/uso terapéutico , Receptores de Somatotropina/genética , Acromegalia/tratamiento farmacológico , Adulto , Anciano , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana Edad , Oligonucleótidos/administración & dosificación , Oligonucleótidos/efectos adversos , ARN Mensajero/antagonistas & inhibidores , Receptores de Somatotropina/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Acromegaly is associated with high morbidity and elevated mortality when not adequately treated. Surgery is the first-line treatment for most patients as it is the only one that can lead to immediate cure. In patients who are not cured by surgery, treatment is currently based on a trial-and-error approach. First-generation somatostatin receptor ligands (fg-SRL) are initiated for most patients, although approximately 25% of patients present resistance to this drug class. Some biomarkers of treatment outcome are described in the literature, with the aim of categorizing patients into different groups to individualize their treatments using a personalized approach. In this review, we will discuss the current status of precision medicine for the treatment of acromegaly and future perspectives on the use of personalized medicine for this purpose.
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Acromegalia/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Medicina de Precisión , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análogos & derivados , Humanos , Resultado del TratamientoRESUMEN
Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, 'Combo SSA' 768 patients (38%); DA combined with pegvisomant, 'Combo DA' 123 (6%); pegvisomant monotherapy, 'Peg mono' 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.
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Acromegalia/tratamiento farmacológico , Agonistas de Dopamina/administración & dosificación , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/administración & dosificación , Acromegalia/sangre , Acromegalia/diagnóstico , Adulto , Anciano , Estudios Transversales , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/antagonistas & inhibidores , Hormona de Crecimiento Humana/sangre , Humanos , Masculino , Persona de Mediana Edad , Receptores de Somatotropina/sangre , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized.