RESUMEN
BACKGROUND: A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves' orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated. METHODS: We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves' disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups. RESULTS: Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = - 0.376, 95% CI: from - 0.373 to - 0.631; P = 0.005), the significance of which remains to be investigated. CONCLUSIONS: Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.
Asunto(s)
Autoanticuerpos/sangre , Biomarcadores/sangre , Enfermedad de Graves/sangre , Oftalmopatía de Graves/sangre , Receptores de Somatomedina/inmunología , Adolescente , Adulto , Anciano , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Enfermedad de Graves/inmunología , Enfermedad de Graves/patología , Oftalmopatía de Graves/inmunología , Oftalmopatía de Graves/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Receptor IGF Tipo 1 , Adulto JovenRESUMEN
BACKGROUND/OBJECTIVES: Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves' disease, remains a disfiguring and potentially blinding condition. Here, the author reviews the role of insulin-like growth factor-I receptor pathway in TAO and how it might be therapeutically targeted. METHODS: The recent literature is reviewed. RESULTS: TAO involves reactivity of orbital connective tissues and their remodeling. While many of the details concerning the pathogenesis of TAO remain to be determined, several insights have come to light recently. Among them is the apparent involvement of IGF-IR. This receptor protein, a membrane-spanning tyrosine kinase receptor can form both physical and functional complexes with the thyrotropin receptor (TSHR). This is notable because TSHR is the established primary autoantigen in Graves' disease. IGF-IR activity is critical to signaling downstream from both IGF-IR and TSHR. In addition, antibodies against IGF-IR have been detected in patients with Graves' disease and in rodent models of TAO. Evidence has been put forward that these antibodies may act directly on IGF-IR, perhaps in some manner activating the receptor. These experimental observations have led to the development of a novel therapy for active TAO, utilizing a monoclonal anti-IGF-IR inhibitory antibody which had been produced originally as treatment for cancer. The agent, teprotumumab was recently evaluated in a clinical trial and found to be highly effective and relatively well-tolerated. It is currently undergoing assessment in a follow-up trial. CONCLUSIONS: Should the current study yield similarly encouraging results, it is possible that teprotumumab will emerge as a paradigm-shifting medical therapy for TAO.
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Autoantígenos/inmunología , Oftalmopatía de Graves/inmunología , Receptores de Somatomedina/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Autoanticuerpos/sangre , Congresos como Asunto , Tejido Conectivo/patología , Oftalmopatía de Graves/tratamiento farmacológico , Humanos , Órbita/patología , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Tirotropina/inmunologíaRESUMEN
I was privileged to be one of the co-chairs, along with Professor Tim Sullivan (Brisbane, Australia), for the Cambridge Ophthalmological Society (COS) annual international symposium, which, this year, was dedicated to thyroid eye disease (TED). Together with the organisers, Miss Rachna Murthy and Professor Keith Martin from COS, we compiled an impressive programme covering all aspects of the condition from events happening in a single orbital cell to improved surgical approaches.
Asunto(s)
Oftalmopatía de Graves , Tejido Adiposo/metabolismo , Animales , Autoanticuerpos/sangre , Autoantígenos/inmunología , Congresos como Asunto , Modelos Animales de Enfermedad , Oftalmopatía de Graves/inmunología , Oftalmopatía de Graves/fisiopatología , Oftalmopatía de Graves/terapia , Humanos , Oftalmología/organización & administración , Receptor IGF Tipo 1 , Receptores de Somatomedina/inmunología , Receptores de Tirotropina/inmunología , Sociedades Médicas/organización & administraciónRESUMEN
The insulin/insulin-like growth factor 1 (IGF1) signaling pathways are implicated in longevity and in progression of Alzheimer's disease. Previously, we showed that insulin-like growth factor 1 receptor (IGF1R) and downstream signaling transcripts are reduced in astrocytes in human brain with progression of Alzheimer's neuropathology and developed a model of IGF1 signaling impairment in human astrocytes using an IGF1R-specific monoclonal antibody, MAB391. Here, we have established a novel human astrocyte-neuron co-culture system to determine whether loss of astrocytic IGF1R affects their support for neurons. Astrocyte-neuron co-cultures were developed using human primary astrocytes and differentiated Lund Human Mesencephalic Cells (LUHMES). Neurite outgrowth assays, performed to measure astrocytic support for neurons, showed astrocytes provided contact-mediated support for neurite outgrowth. Loss of IGF1R did not affect neurite outgrowth under control conditions but when challenged with hydrogen peroxide IGF1R-impaired astrocytes were less able to protect LUHMES. To determine how loss of IGF1R affects neuronal support MAB391-treated astrocytes were FACS sorted from GFP-LUHMES and their transcriptomic profile was investigated using microarrays. Changes in transcripts involved in astrocyte energy metabolism were identified, particularly NDUFA2 and NDUFB6, which are related to complex I assembly. Loss of complex I activity in MAB391-treated astrocytes validated these findings. In conclusion, reduced IGF1 signaling in astrocytes impairs their support for neurons under conditions of stress and this is associated with defects in the mitochondrial respiratory chain in astrocytes.
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Astrocitos/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Neuronas/metabolismo , Receptores de Somatomedina/metabolismo , Anticuerpos Monoclonales/administración & dosificación , Técnicas de Cocultivo/métodos , Metabolismo Energético , Humanos , Proyección Neuronal , Estrés Oxidativo , Cultivo Primario de Células , Receptor IGF Tipo 1 , Receptores de Somatomedina/inmunología , TranscriptomaRESUMEN
PURPOSE: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS: Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION: The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE: This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Biomarcadores de Tumor/metabolismo , Relación Dosis-Respuesta a Droga , Everolimus/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Panitumumab/administración & dosificación , Receptor IGF Tipo 1 , Receptores de Somatomedina/inmunologíaRESUMEN
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ-IL-17A-Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4+ T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.
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Exosomas/inmunología , MicroARNs/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Exosomas/genética , Exosomas/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Masculino , MicroARNs/genética , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor IGF Tipo 1 , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Somatomedina/genética , Receptores de Somatomedina/inmunología , Receptores de Somatomedina/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/inmunología , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Linfocitos T Reguladores/metabolismo , Transcriptoma/inmunologíaRESUMEN
The signaling pathways of interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) play an important role in the progression of lung cancer, and this study aimed to explore whether they can synergistically promote the progression of non-small cell lung cancer (NSCLC). We found that IL-6, glycoprotein 130 (GP130), IGF-1 and IGF-1R were highly expressed in NSCLC (p = .000), and there was the correlation between GP130, IGF-1, and IGF-1R (p < .01). The overall survival of patients with the co-expression of GP130 and IGF-1R was significantly shorter (p = .0360). Co-stimulation of IL-6 and IGF-1 resulted in significantly enhanced in cell proliferation, (p < .05), invasion (p < .05), cycle (p < .05), apoptosis (p < .05), and the expression of signal molecules (GP130, IGF-1R, p-AKT, and p-ERK1/2) (all p < .05) in NSCLC cells. This experiment revealed that IL-6 and IGF-1 can synergistically promote the progression of NSCLC. The high expression of GP130 and IGF-1R is an independent risk factor for poor prognosis patients, and it is helpful to find a more accurate target for targeted therapy in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Interleucina-6/metabolismo , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Movimiento Celular/inmunología , Proliferación Celular , Receptor gp130 de Citocinas/inmunología , Receptor gp130 de Citocinas/metabolismo , Progresión de la Enfermedad , Humanos , Factor I del Crecimiento Similar a la Insulina/inmunología , Interleucina-6/inmunología , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Pronóstico , Receptor IGF Tipo 1 , Receptores de Somatomedina/inmunología , Receptores de Somatomedina/metabolismo , Análisis de SupervivenciaAsunto(s)
Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Adolescente , Muerte , Epigénesis Genética , Humanos , Masculino , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/química , Proteína Proto-Oncogénica c-fli-1/antagonistas & inhibidores , Proteína Proto-Oncogénica c-fli-1/química , Interferencia de ARN , Proteína EWS de Unión a ARN/antagonistas & inhibidores , Proteína EWS de Unión a ARN/química , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Receptores de Somatomedina/inmunología , Sarcoma de Ewing/metabolismoRESUMEN
BACKGROUND Preferentially expressed antigen of melanoma (PRAME) is known as a tumor-associated antigen that is altered in a variety of malignancies, including lung cancer. However, the role of PRAME in lung cancer remains unclear. MATERIAL AND METHODS We analyzed the expression of PRAME in human lung adenocarcinomas and studied the function of PRAME using small interfering RNA (siRNA)-induced gene knockdown in lung cancer cell lines PC9 and A549. RESULTS We found that PRAME expression is down-regulated in lung adenocarcinomas. Knockdown of PRAME promoted proliferation and suppressed apoptosis of PC9 and A549 cells. CONCLUSIONS In line with its roles in controlling cell growth, RPAME regulates multiple critical cell-growth related genes, including IGF1R oncogene. IGF1R up-regulation contributes to increase of cell growth upon the knockdown of PRAME. Taken together, our results suggest that PRAME has inhibitory roles in lung cancer.
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Adenocarcinoma/inmunología , Antígenos de Neoplasias/biosíntesis , Neoplasias Pulmonares/inmunología , Células A549 , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Apoptosis/fisiología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular/fisiología , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Genes Supresores de Tumor , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Receptores de Somatomedina/inmunología , Transfección , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the inhibitory effect of high concentration insulin on K562 cell proliferation and its underlying mechanism. METHODS: K562 cells were treated by different concentration of insulin and/or anti-IGF-1R antibody (IGF-1R-Ab), MTT assay and flow cytometry were used to detect the K562 cells proliferation and apoptosis, respectivety; Western blot was used to measure the expression and phosphorylation level of IGE-IR, Akt, Erk1/2 in K562 cells under the different concentration of insulin. RESULTS: MTT assay showed that less than 40 mU/ml insulin could promote K562 cell proliferation, while high concentration (> 40 mU/ml) insulin has been shown to inhibit K562 cell proliferation; Flow cytometry showed that 40 mU/ml insulin suppressed K562 cell apoptosis (P < 0.05), while 200 mU/ml insulin could significantly induce K562 cell apoptosis (P < 0.01); 0.01 to 1.0 µg/ml IGF-1R-Ab has significantly enhanced the inhibitory and inducing effects of high concentration (> 40 mU/ml) of insulin on K562 cell proliferation and apoptosis respectively (r = 0.962, P < 0.001); Western blot showed that after K562 cells were treated with different concentrations of insulin ERK, and the p-ERK expression did not change significantly, after K562 cells were treated with 200 mU/ml insulin, the expression of IGF-1R and AKT also not were changed obviously, while the phosphorylation level of IGF-1R and AKT increased. CONCLUSION: High concentration (>40 mU/ml) of insulin inhibits K562 cell proliferation and induces its apoptosis, and its mechanism may be related with the binding IGF-1R by insulin, competitively inhibiting the binding of IGF-1 and IGF-1R, the blocking the transduction of PI3K/AKT signal pathway.
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Anticuerpos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Insulina/farmacología , Transducción de Señal/efectos de los fármacos , Medios de Cultivo/química , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células K562 , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Somatomedina/inmunologíaRESUMEN
Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
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Células Dendríticas/inmunología , Proteínas de Neoplasias/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Receptores de Somatomedina/inmunología , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Supervivencia Celular , Células Dendríticas/patología , Femenino , Humanos , Masculino , Ratones , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor IGF Tipo 1 , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/inmunología , Receptores de Somatomedina/genética , Transducción de Señal/genética , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Receptor occupancy (RO) assays measure drug target engagement, and are used as pharmacodynamic (PD) biomarkers. RO assays are commonly performed by flow cytometry and often require multiplexing for assessment of multiple PD biomarkers when specimen volumes are limited. We present multiplexed RO assays for an IGF1R-EGFR bispecific antibody (Bs-Ab) and a CTLA4-Ig recombinant fusion protein to demonstrate key considerations for accurate RO assessment. METHODS: RO in cynomolgus monkeys was determined in whole blood using flow cytometry. Free and total receptors were measured using anti-receptor fluorescence-labeled detection reagents, competitive and noncompetitive to drug, respectively. RESULTS: RO of IGF1R was examined as PD for Bs-Ab, since IGF1R was expressed on blood cells. Multiplexed measurements of free and total IGF1R showed that IGF1R expression measured by total receptor was highly variable, impacting interpretation of free-IGF1R. Normalization of free-over-total IGF1R measurements compensated for variability of receptor expression allowing for accurate RO assessment. RO of CTLA4-Ig, a recombinant fusion protein targeting CD80 and CD86 receptors, was multiplexed to simultaneously measure target engagements for both receptors. Both RO methods demonstrated specificity of receptor measurements without cross-reactivity to each other in multiplexed formats. RO methods were used for evaluation of PD activity of Bs-Ab and CTLA4-Ig in cynomolgus monkeys. In both cases, RO results showed dose-dependent target engagement, corresponding well to the pharmacokinetics. CONCLUSIONS: Multiplexed RO methods allowed accurate assessment of PD activity for Bs-Ab and CTLA4-Ig, facilitating development of these biopharmaceuticals from preclinical to clinical stages.
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Anticuerpos Biespecíficos/inmunología , Receptores ErbB/inmunología , Citometría de Flujo , Receptores de Somatomedina/inmunología , Anticuerpos Biespecíficos/uso terapéutico , Antígeno B7-1/inmunología , Antígeno B7-1/uso terapéutico , Biomarcadores , Antígeno CTLA-4/inmunología , Receptores ErbB/uso terapéutico , Humanos , Inmunoconjugados/inmunología , Inmunosupresores/inmunología , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Receptor IGF Tipo 1 , Receptores de Somatomedina/uso terapéutico , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Receptores de Somatomedina/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/administración & dosificación , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Células MCF-7/patología , Ratones Endogámicos BALB C , Terapia Molecular Dirigida/métodos , Quinolinas/administración & dosificación , Receptor IGF Tipo 1 , Receptores de Somatomedina/inmunología , Trastuzumab/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND AIMS: The prevalence of lung cancer is increasing in the recent decades. The underlying mechanism is unclear. The insulin-like growth factor (IGF) and p53 protein are important molecules involving the tumor immunity. This study aims to investigate the role of IGF intervene the radiation-induced lung cancer apoptosis. METHODS: Lung cancer cells were isolated from surgically removed lung cancer tissue. The lung cancer cell lines, A549 cells and H23 cells were irradiated. The expression of IGF1 receptor (IGF1R) by the lung cancer cells, and apoptosis, were assessed by flow cytometry. RESULTS: The results showed that human lung cancer cells expressed IGF1R. IGF1R played a critical role in the radiation-induced lung cancer cell apoptosis. The histone deacetylase-1 (HDAC1) phosphorylation was up regulated by irradiation. The phosphorylated HDAC1 bound the p53 promoter to inhibit the gene transcription, which was abolished by the presence of an inhibitor of HDAC1 or a STAT3 inhibitor. CONCLUSION: The data suggest that activation of IGF1R plays a critical role in the radioresistance, which can be prevented in the presence of the inhibitors of HDAC1 or STAT3 inhibitors.
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Apoptosis/inmunología , Rayos gamma , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias Pulmonares/inmunología , Proteínas de Neoplasias/inmunología , Tolerancia a Radiación/inmunología , Receptores de Somatomedina/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/inmunología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Proteínas de Neoplasias/antagonistas & inhibidores , Tolerancia a Radiación/efectos de los fármacos , Receptor IGF Tipo 1 , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/inmunologíaRESUMEN
Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13(+)CD133(+) cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13(+)CD133(+) cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation.
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Conductos Biliares/citología , Hepatocitos/citología , Células Madre Pluripotentes Inducidas/citología , Proteínas de la Membrana/metabolismo , Células 3T3 , Animales , Biomarcadores/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular , Línea Celular , Proliferación Celular , Citocinas/farmacología , Células Nutrientes/metabolismo , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Citometría de Flujo , Humanos , Ratones , Receptor ErbB-2/antagonistas & inhibidores , Receptor IGF Tipo 1/biosíntesis , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/inmunología , Receptores de Somatomedina/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Somatomedinas/metabolismo , Receptor de TWEAKRESUMEN
PURPOSE: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. EXPERIMENTAL DESIGN: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. RESULTS: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity. CONCLUSIONS: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Sirolimus/análogos & derivados , Adulto , Anciano , Animales , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Humanos , Persona de Mediana Edad , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/inmunología , Receptores de Somatomedina/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Type 1 insulin-like growth factor receptor (IGF-1R) is a promising therapeutic target for cancer treatment. A single-chain variable fragment (scFv) against human IGF-1R forms inclusion body when expressed in periplasmic space of E. coli routinely. Here, we described that co-expression of appropriate disulfide bonds (Dsb) proteins known to catalyze the formation and isomerization of Dsb can markedly recover the soluble expression of target scFv in E. coli. A 50 % recovery in solubility of the scFv was observed upon co-expression of DsbC alone, and a maximum solubility (80 %) was obtained when DsbA and DsbC were co-expressed in combination. Furthermore, the soluble scFv present full antigen-binding activity with IGF-1R, suggesting its correct folding. This study also suggested that the selection of Dsb proteins should be tested case-by-case if the approach of co-expression of Dsb system is adopted to address the problem of insoluble expression of proteins carrying Dsb.
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Biotecnología/métodos , Proteínas de Escherichia coli/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Anticuerpos de Cadena Única/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Unión Proteica , Pliegue de Proteína , Receptores de Somatomedina/inmunología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Anticuerpos de Cadena Única/química , Anticuerpos de Cadena Única/genética , SolubilidadAsunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumores de Células Gigantes/tratamiento farmacológico , Articulación del Hombro/patología , Sirolimus/análogos & derivados , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Everolimus , Tumores de Células Gigantes/diagnóstico , Tumores de Células Gigantes/patología , Humanos , Cápsula Articular/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/inmunología , Sirolimus/administración & dosificación , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Tendones/patología , Resultado del TratamientoRESUMEN
The insulin-like growth factor (IGF) family and the IGF-1 receptor (IGF-1R) play an important role in cancer. This intricate and complex signaling pathway provides many opportunities for therapeutic intervention, and several novel therapeutics aimed at the IGF-1R, particularly monoclonal antibodies and small molecule tyrosine kinase inhibitors, are under clinical investigation. This article provides a patent overview of the IGF signaling pathway and its complexity, addresses the justification for the use of IGF-1R-targeted therapy, and reviews the results of in vivo and in vitro novel therapeutics. Over the past year, the completion of several phase I, II, and III trials have provided interesting new information about the clinical activity of these novel compounds, particularly CP-751,871, IMC-A12, R1507, AMG-479, AVE-1642, MK-0646, XL-228, OSI-906, and BMS-754807. We review the important preliminary results from clinical trials with these compounds and conclude with a discussion about future therapeutic efforts.
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Anticuerpos Monoclonales/uso terapéutico , Descubrimiento de Drogas/tendencias , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Somatomedina/antagonistas & inhibidores , Transducción de Señal/inmunología , Somatomedinas/antagonistas & inhibidores , Animales , Ensayos Clínicos como Asunto/tendencias , Humanos , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Somatomedina/inmunología , Somatomedinas/inmunologíaRESUMEN
Nowadays the lack of exercise and improper eating habits are main characteristics of modern life style. This favors not only formation of type 2 diabetes or cardiovascular diseases, but also increaseas the incidence and prevalence of malignant tumors. Today there are many epidemiologic trials that demonstrate the connection between type 2 diabetes and formation of several malignomas. Its cause should be searched in common paths of pathologic processes. One of this is the birth of hyperinsulinsulinemia, which accompanies insulin resistance. Hyperinsulinemia of the host leads to increased glucose uptake in the highly insuline sensitive tumor cells which supports tumor growth. This makes type 2 diabetes a metabolic state favoring tumor formation, suggesting a potential application of oral insulin sensitizers in cancer therapy. Currently several international trials are testing the anti-tumor activity of metformin and thiazolidinedions (TZD). Besides this, encouraging results were obtained with the use of anti-IGFR antibodies in the treatment of tumors. A common therapy of diabetes and tumor may lead to new possibilities in the treatment of malignant tumor diseases. By doing this we could be able to weaken the tumor and strengthen the body, enabling it to fight against cancer. Bánhegyi RJ, Rus-Gal PO, Nagy AK, Martyin T, Varga R, Pikó B. Correlation between type 2 diabetes and malignant tumors - new possibilities in the complex therapy of cancers?