RESUMEN
BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP. METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively. RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs. CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.
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Miositis Osificante , Osificación Heterotópica , Femenino , Humanos , Ratones , Animales , Miositis Osificante/genética , Miositis Osificante/terapia , Osificación Heterotópica/terapia , Osificación Heterotópica/genética , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/farmacología , Transducción de Señal , Ratones Transgénicos , Mutación , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo II/farmacologíaRESUMEN
BACKGROUND: Multitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the efficacy of mTKIs in colorectal cancer (CRC) is limited; the underlined mechanism remains largely elusive. Our study was aimed to find out the resistance mechanism of mTKIs in CRC. METHODS: RNA sequencing was used to identify the expression of Activin A receptor-like type 1 (ACVRL1) under the treatment of mTKIs. Gain/loss-of-function experiments were performed to assess the biological function of ACVRL1 in resistance to mTKIs. The underlying mechanisms of ACVRL1-mediated mTKI resistance were investigated by using liquid chromatography-mass spectrometry assays (LC-MS), co-immunoprecipitation assays (Co-IP), chromatin immunoprecipitation assays, ubiquitination assays, dual luciferase reporter assays, etc. RESULTS: RNA sequencing identified the activation of ACVRL1 under the treatment of mTKIs in CRC cells. ACVRL1 knockdown and overexpression significantly affects the sensitivity of CRC cells to mTKIs both in vitro and vivo. Mechanistically, we found the ß-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediated the activation of ACVRL1. Furthermore, LC-MS assays indicated the interaction between ACVRL1 and glutathione peroxidase 2(GPX2) protein. IP assay defined ACVRL1 truncation (282-503aa) could be responsible for interacting with GPX2, and rescue experiments with ACVRL1 truncations confirmed the importance of this interaction in driving mTKI resistance. Co-IP assays confirmed that ACVRL1 associates with ubiquitin-specific peptidase 15(USP15) which directly deubiquinates GPX2 at the K187(K, lysine) site, leading to the accumulation of GPX2 protein. Rescue experiments performed with the lysine mutants in GPX2 CRISPR knockout cell model confirmed the importance of GPX2 K187 mutant. As a result, the increased ROS clearance and decreased cell apoptosis eventually lead to mTKI resistance in CRC. CONCLUSIONS: Our results demonstrate that the Wnt/ß-catenin/KCNQ1OT1/miR-7-5p/ACVRL1/GPX2 biological axis plays a vital role in CRC, targeting which may be an effective approach for overcoming mTKI resistance.
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Neoplasias Colorrectales , MicroARNs , Humanos , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacología , Lisina/genética , Lisina/metabolismo , Lisina/farmacología , MicroARNs/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo II/farmacología , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/farmacologíaRESUMEN
The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
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Receptores de Activinas Tipo II/farmacología , Quimiocina CXCL12/metabolismo , Hematopoyesis , Células Madre Hematopoyéticas/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión/farmacología , Adulto , Anciano , Animales , Estudios de Casos y Controles , Quimiocina CXCL12/genética , Hematínicos/farmacología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Proteína Smad2/genética , Proteína Smad2/metabolismo , Células Tumorales Cultivadas , Pez CebraRESUMEN
Luspatercept (Reblozyl®), a first-in-class erythroid maturation agent, is approved in several countries worldwide for the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS), who have failed prior erythropoiesis-stimulating therapy, or ß-thalassaemia. In pivotal, placebo-controlled, phase III trials, subcutaneous luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS or ß-thalassaemia. Luspatercept had a generally manageable tolerability profile in clinical trials. Adverse events of special interest include thromboembolic events, hypertension and bone pain. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS or ß-thalassaemia.
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Receptores de Activinas Tipo II/uso terapéutico , Anemia/etiología , Transfusión de Eritrocitos/efectos adversos , Hematínicos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Síndromes Mielodisplásicos/terapia , Proteínas Recombinantes de Fusión/uso terapéutico , Talasemia beta/terapia , Receptores de Activinas Tipo II/efectos adversos , Receptores de Activinas Tipo II/farmacología , Ensayos Clínicos Fase III como Asunto , Hematínicos/efectos adversos , Hematínicos/farmacología , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-ß superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.
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Receptores de Activinas Tipo II/farmacología , Receptores de Activinas Tipo I/farmacología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/farmacología , Músculo Esquelético/metabolismo , Trastornos Musculares Atróficos/tratamiento farmacológico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Proteínas Recombinantes de Fusión/farmacología , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo II/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/patología , Trastornos Musculares Atróficos/genética , Trastornos Musculares Atróficos/metabolismo , Trastornos Musculares Atróficos/patología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Proteínas Recombinantes de Fusión/genéticaRESUMEN
Transforming growth factor beta (TGF-ß) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-ß ligands preventing them from binding to Type II TGF-ß receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.
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Receptores de Activinas Tipo II/farmacología , Fragmentos Fc de Inmunoglobulinas/farmacología , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión/farmacología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Receptores de Activinas Tipo II/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Resultado del TratamientoRESUMEN
Significance: Iron is an essential element required for sustaining a normal healthy life. However, an excess amount of iron in the bloodstream and tissue generates toxic hydroxyl radicals through Fenton reactions. Henceforth, a balance in iron concentration is extremely important to maintain cellular homeostasis in both normal hematopoiesis and erythropoiesis. Iron deficiency or iron overload can impact hematopoiesis and is associated with many hematological diseases. Recent Advances: The mechanisms of action of key iron regulators such as erythroferrone and the discovery of new drugs, such as ACE-536/luspatercept, are of potential interest to treat hematological disorders, such as ß-thalassemia. New therapies targeting inflammation-induced ineffective erythropoiesis are also in progress. Furthermore, emerging evidences support differential interactions between iron and its cellular antioxidant responses of hematopoietic and neighboring stromal cells. Both iron and its systemic regulator, such as hepcidin, play a significant role in regulating erythropoiesis. Critical Issues: Significant pre-clinical studies are on the way and new drugs targeting iron metabolism have been recently approved or are undergoing clinical trials to treat pathological conditions with impaired erythropoiesis such as myelodysplastic syndromes or ß-thalassemia. Future Directions: Future studies should explore how iron regulates hematopoiesis in both benign and malignant conditions. Antioxid. Redox Signal. 35, 415-432.
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Receptores de Activinas Tipo II/farmacología , Eritropoyesis/efectos de los fármacos , Fragmentos Fc de Inmunoglobulinas/farmacología , Hierro/metabolismo , Síndromes Mielodisplásicos/tratamiento farmacológico , Hormonas Peptídicas/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Talasemia beta/tratamiento farmacológico , Humanos , Síndromes Mielodisplásicos/metabolismo , Talasemia beta/metabolismoRESUMEN
In ß-thalassaemia, anaemia results from ineffective erythropoiesis characterized by inhibition of late-stage erythroid differentiation. We earlier used luspatercept and RAP-536 protein traps for certain Smad2/3-pathway ligands to implicate Smad2/3-pathway overactivation in dysregulated erythroid differentiation associated with murine ß-thalassaemia and myelodysplasia. Importantly, luspatercept alleviates anaemia and has been shown to reduce transfusion burden in patients with ß-thalassaemia or myelodysplasia. Here, we investigated the molecular mechanisms underlying luspatercept action and pSmad2/3-mediated inhibition of erythroid differentiation. In murine erythroleukemic (MEL) cells in vitro, ligand-mediated overactivation of the Smad2/3 pathway reduced nuclear levels of GATA-1 (GATA-binding factor-1) and its transcriptional activator TIF1γ (transcription intermediary factor 1γ), increased levels of reactive oxygen species, reduced cell viability and haemoglobin levels, and inhibited erythroid differentiation. Co-treatment with luspatercept in MEL cells partially or completely restored each of these. In ß-thalassaemic mice, RAP-536 up-regulated Gata1 and its target gene signature in erythroid precursors determined by transcriptional profiling and gene set enrichment analysis, restored nuclear levels of GATA-1 in erythroid precursors, and nuclear distribution of TIF1γ in erythroblasts. Bone marrow cells from ß-thalassaemic mice treated with luspatercept also exhibited restored nuclear availability of GATA-1 ex vivo. Our results implicate GATA-1, and likely TIF1γ, as key mediators of luspatercept/RAP-536 action in alleviating ineffective erythropoiesis.
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Receptores de Activinas Tipo II/farmacología , Diferenciación Celular , Células Eritroides/patología , Factor de Transcripción GATA1/metabolismo , Fragmentos Fc de Inmunoglobulinas/farmacología , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Talasemia beta/patología , Anemia/complicaciones , Anemia/tratamiento farmacológico , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Eritroblastos , Células Eritroides/efectos de los fármacos , Hemoglobinas/metabolismo , Leucemia Eritroblástica Aguda/patología , Ligandos , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Talasemia beta/complicaciones , Talasemia beta/genéticaRESUMEN
Anemia is the most common clinical manifestation of myelodysplastic syndrome (MDS), and most patients become red blood cell transfusion dependent. Defective erythropoiesis includes impaired terminal erythroid maturation. There are limited options for treatments of anemia in lower-risk MDS after failure of erythroid-stimulating agents. Luspatercept is an activin receptor type IIB fusion ligand trap novel agent. Luspatercept showed promising activity for treating anemia in patients with MDS with ring sideroblast subtypes. This article reviews the mechanism of impaired erythropoiesis in MDS. It summarizes clinical data with luspatercept and foresees how to best use this treatment in practice.
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Receptores de Activinas Tipo II/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo II/farmacología , Anemia/diagnóstico , Anemia/etiología , Ensayos Clínicos como Asunto , Eritropoyesis/efectos de los fármacos , Eritropoyesis/genética , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Mutations in at least 12 genes are responsible for a group of congenital skeletal muscle diseases known as nemaline myopathies (NMs). NMs are associated with a range of clinical symptoms and pathological changes often including the presence of cytoplasmic rod-like structures (nemaline bodies) and myofiber hypotrophy. Our recent work has identified a variable degree of behavioral benefit when treating 2 NM mouse models due to mutations in Acta1 with myostatin inhibition. This study is focused on the effects of delivering ActRIIB-mFc (Acceleron; a myostatin inhibitor) to the nebulin conditional knockout KO (Neb cKO) mouse model of NM. Treatment of Neb cKO mice with ActRIIB-mFc did not produce increases in weight gain, strength, myofiber size, or hypertrophic pathway signaling. Overall, our studies demonstrate a lack of response in Neb cKO mice to myostatin inhibition, which differs from the response observed when treating other NM models.
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Receptores de Activinas Tipo II/farmacología , Fuerza Muscular/efectos de los fármacos , Miopatías Nemalínicas , Miostatina/antagonistas & inhibidores , Aumento de Peso/efectos de los fármacos , Animales , Ratones , Ratones Noqueados , Proteínas Musculares/deficiencia , Debilidad Muscular/genéticaRESUMEN
RATIONALE: Although many familial cases of pulmonary arterial hypertension exhibit an autosomal dominant mode of inheritance with the majority having mutations in essential constituents of the BMP (bone morphogenetic protein) signaling, the specific contribution of the long-term loss of signal transduction triggered by the BMPR2 (type 2 BMP receptor) remains poorly characterized. OBJECTIVE: To investigate the role of BMP9, the main ligand of ALK1 (Activin receptor-like kinase 1)/BMPR2 heterocomplexes, in pulmonary hypertension. METHOD AND RESULTS: The absence of BMP9 in Bmp9-/- mice and its inhibition in C57BL/6 mice using neutralizing anti-BMP9 antibodies substantially prevent against chronic hypoxia-induced pulmonary hypertension judged by right ventricular systolic pressure measurement, right ventricular hypertrophy, and pulmonary distal arterial muscularization. In agreement with these observations, we found that the BMP9/BMP10 ligand trap ALK1ECD administered in monocrotaline or Sugen/hypoxia (SuHx) rats substantially attenuate proliferation of pulmonary vascular cells, inflammatory cell infiltration, and regresses established pulmonary hypertension in rats. Our data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin. We reproduced these in vitro observations in mice chronically exposed to hypoxia, with Bmp9-/- mice exhibiting lower mRNA levels of the vasoconstrictor peptide ET-1 (endothelin-1) and higher levels of the 2 potent vasodilator factors apelin and ADM (adrenomedullin) compared with Bmp9+/+ littermates. CONCLUSIONS: Taken together, our data indicate that the loss of BMP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.
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Factor 2 de Diferenciación de Crecimiento/antagonistas & inhibidores , Hipertensión Pulmonar/prevención & control , Receptores de Activinas Tipo II/farmacología , Animales , Células Cultivadas , Endotelina-1/genética , Factor 2 de Diferenciación de Crecimiento/fisiología , Humanos , Hipoxia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas WistarRESUMEN
LESSONS LEARNED: Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted. BACKGROUND: Targeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC). METHODS: In this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response. RESULTS: A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease. CONCLUSION: The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.
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Receptores de Activinas Tipo II/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Sorafenib/uso terapéutico , Receptores de Activinas Tipo II/farmacología , Antineoplásicos/farmacología , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/farmacología , Sorafenib/farmacologíaRESUMEN
BACKGROUND: Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered. METHODS: The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non-muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B-Fc). Treatment with sACVR2B-Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non-muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking. RESULTS: Blocking of ACVR2 ligands improved survival in tumour-bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro-inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B-Fc was not explained by decreased markers of myeloid-derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late-endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis. CONCLUSIONS: The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non-muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late-endosomes in cancer opens up new research questions and possible treatment options for cachexia.
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Receptores de Activinas Tipo II/farmacología , Caquexia/metabolismo , Hígado/efectos de los fármacos , Proteínas Recombinantes/farmacología , Bazo/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Receptores de Activinas Tipo II/uso terapéutico , Animales , Biomarcadores , Caquexia/tratamiento farmacológico , Caquexia/etiología , Caquexia/patología , Línea Celular Tumoral , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Mediadores de Inflamación , Estimación de Kaplan-Meier , Hígado/metabolismo , Masculino , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Transporte de Proteínas/efectos de los fármacos , Proteínas Recombinantes/uso terapéutico , Bazo/inmunología , Bazo/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder primarily due to mutations in the type I collagen genes (COL1A1 and COL1A2), leading to compromised biomechanical integrity in type I collagen-containing tissues such as bone. Bone is inherently mechanosensitive and thus responds and adapts to external stimuli, such as muscle mass and contractile strength, to alter its mass and shape. Myostatin, a member of the TGF-ß superfamily, signals through activin receptor type IIB to negatively regulate muscle fiber growth. Because of the positive impact of myostatin deficiency on bone mass, we utilized a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein in two molecularly distinct OI mouse models (G610C and oim) and evaluated their bone properties. Wild-type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with either vehicle (Tris-buffered saline) or sActRIIB-mFc (10 mg/kg). Femurs of sActRIIB-mFc-treated mice exhibited increased trabecular bone volume regardless of genotype, whereas the cortical bone microarchitecture and biomechanical strength were only improved in WT and +/G610C mice. Dynamic histomorphometric analyses suggest the improved cortical bone geometry and biomechanical integrity reflect an anabolic effect due to increased mineral apposition and bone formation rates, whereas static histomorphometric analyses supported sActRIIB-mFc treatment also having an anti-catabolic impact with decreased osteoclast number per bone surface on trabecular bone regardless of sex and genotype. Together, our data suggest that sActRIIB-mFc may provide a new therapeutic direction to improve both bone and muscle properties in OI. © 2018 American Society for Bone and Mineral Research.
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Receptores de Activinas Tipo II/uso terapéutico , Huesos/patología , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis Imperfecta/patología , Receptores de Activinas Tipo II/farmacología , Animales , Biomarcadores/sangre , Fenómenos Biomecánicos , Huesos/fisiopatología , Modelos Animales de Enfermedad , Femenino , Fémur/patología , Masculino , Ratones Endogámicos C57BL , Osteoblastos/metabolismo , Osteoblastos/patología , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteogénesis Imperfecta/sangre , Osteogénesis Imperfecta/fisiopatología , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Solubilidad , Torsión MecánicaRESUMEN
Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.
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Enfermedad de Huntington/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Miostatina/antagonistas & inhibidores , Receptores de Activinas Tipo II/farmacología , Animales , Peso Corporal/efectos de los fármacos , Fuerza de la Mano/fisiología , Proteína Huntingtina/química , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/fisiopatología , Masculino , Ratones , Músculo Esquelético/patología , Atrofia Muscular/complicaciones , Atrofia Muscular/prevención & control , Agregado de Proteínas/efectos de los fármacosRESUMEN
Fractures still present a significant burden to patients due to pain and periods of unproductivity. Numerous growth factors have been identified to regulate bone remodeling. However, to date, only the bone morphogenetic proteins (BMPs) are used to enhance fracture healing in clinical settings. Activins are pleiotropic growth factors belonging to the TGF-ß superfamily. We and others have recently shown that treatment with recombinant fusion proteins of activin receptors greatly increases bone mass in different animal models by trapping activins and other ligands thus inhibiting their signaling pathways. However, their effects on fracture healing are less known. Twelve-week old male C57Bl mice were subjected to a standardized, closed tibial fracture model. Animals were divided into control and treatment groups and were administered either PBS control or a soluble activin type IIB receptor (ActRIIB-Fc) intraperitoneally once a week for a duration of two or four weeks. There were no significant differences between the groups at two weeks but we observed a significant increase in callus mineralization in ActRIIB-Fc-treated animals by microcomputed tomography imaging at four weeks. Bone volume per tissue volume was 60%, trabecular number 55% and bone mineral density 60% higher in the 4-week calluses of the ActRIIB-Fc-treated mice (p<0.05 in all). Biomechanical strength of 4-week calluses was also significantly improved by ActRIIB-Fc treatment as stiffness increased by 64% and maximum force by 45% (p<0.05) compared to the PBS-injected controls. These results demonstrate that ActRIIB-Fc treatment significantly improves healing of closed long bone fractures. Our findings support the previous reports of activin receptors increasing bone mass but also demonstrate a novel approach for using ActRIIB-Fc to enhance fracture healing.
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Receptores de Activinas Tipo II/administración & dosificación , Curación de Fractura/efectos de los fármacos , Fracturas de la Tibia/tratamiento farmacológico , Receptores de Activinas Tipo II/farmacología , Animales , Densidad Ósea/efectos de los fármacos , Modelos Animales de Enfermedad , Esquema de Medicación , Inyecciones Intraperitoneales , Masculino , Ratones , Fracturas de la Tibia/diagnóstico por imagen , Resultado del Tratamiento , Microtomografía por Rayos XRESUMEN
Clinical development of anti-angiogenic agents has been a major landmark in cancer therapy for several types of cancers. Signals mediated by both vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-9 and 10 have been implicated in tumor angiogenesis. However, previous studies have shown that targeting the individual signals was not sufficiently effective in retarding tumor growth in certain preclinical and clinical conditions. In the present study, we developed a novel decoy chimeric receptor that traps both VEGF and BMP-9/10. Single targeting of either VEGF or BMP-9/10 signals significantly reduced the formation of tumor vessels in a mouse xenograft model of human pancreatic cancer; however, it did not show significant therapeutic effects on tumor growth. In contrast, dual targeting of the angiogenic signals resulted in more significant inhibition of tumor angiogenesis, leading to delay of tumor growth. Our findings suggest that simultaneous blockade of VEGF and BMP-9/10 signals is a promising therapeutic strategy for the cancers that are resistant to anti-VEGF and BMP-9/10 therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Activinas Tipo II/química , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/farmacología , Receptores de Activinas Tipo II/uso terapéutico , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Proliferación Celular , Femenino , Factor 2 de Diferenciación de Crecimiento/antagonistas & inhibidores , Factor 2 de Diferenciación de Crecimiento/metabolismo , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/farmacología , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/irrigación sanguínea , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/química , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). METHODS: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. RESULTS: ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. CONCLUSION: ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017.
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Receptores de Activinas Tipo II/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Miostatina/antagonistas & inhibidores , Resultado del Tratamiento , Receptores de Activinas Tipo II/farmacocinética , Receptores de Activinas Tipo II/farmacología , Adolescente , Composición Corporal/efectos de los fármacos , Niño , Preescolar , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico por imagen , Caminata/fisiologíaRESUMEN
With the increasing demand for affordable, high-quality meat, livestock and poultry producers must continually find ways to maximize muscle growth in their animals without compromising palatability of the meat products. Muscle mass relies on myoblast proliferation during prenatal or prehatch stages and fiber hypertrophy through protein synthesis and nuclei donation by satellite cells after birth or hatch. Therefore, understanding the cellular and molecular mechanisms of myogenesis and muscle development is of great interest. Myostatin is a well-known negative regulator of muscle growth and development that inhibits proliferation and differentiation in myogenic cells as well as protein synthesis in existing muscle fibers. In this review, various inhibitors of myostatin activity or signaling are examined that may be used in animal agriculture for enhancing muscle growth. Myostatin inhibitors are relevant as potential therapies for muscle-wasting diseases and muscle weakness in humans and animals. Currently, there are no commercial myostatin inhibitors for agriculture or biomedical purposes because the safest and most effective option has yet to be identified. Further investigation of myostatin inhibitors and administration strategies may revolutionize animal production and the medical field.