RESUMEN
OBJECTIVE: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC). DESIGN, SETTING AND PARTICIPANTS: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion. INTERVENTIONS: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation. OUTCOME MEASURES: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab. RESULTS: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types. TRIAL REGISTRATION NUMBER: NCT02608268.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacocinética , Melanoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Anciano de 80 o más AñosRESUMEN
PURPOSE: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors. PATIENTS AND METHODS: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W. RESULTS: Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12-27 months) in colorectal cancer (n = 2), non-small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Combinación de Medicamentos , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Estadificación de Neoplasias , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.
Asunto(s)
Metalotioneína/metabolismo , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Animales , Biomarcadores/metabolismo , Peso Corporal , Tamaño de la Célula , Silenciador del Gen , Glucocorticoides/efectos adversos , Humanos , Hipertrofia , Ratones , Desarrollo de Músculos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Atrofia Muscular , Tamaño de los Órganos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Sarcopenia/metabolismo , Sarcopenia/patología , Sarcopenia/fisiopatología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba , Zinc/metabolismoRESUMEN
Runx2 is a master regulator of bone development and has also been described as an oncogene. Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα), both implicated in bone metabolism and breast cancer, have been shown to share common transcriptional targets. Here, we show that ERα is a positive regulator of Runx2-I transcription. Moreover, ERRα can act as a transcriptional activator of Runx2-I in presence of peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α). In contrast, ERRα behaves as a negative regulator of Runx2-I transcription in presence of PGC-1ß. ERα and ERRα cross-talk via a common estrogen receptor response element on the Runx2-I promoter. In addition, estrogen regulates PGC-1ß that in turn is able to modulate both ERα and ERRα transcriptional activity.
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Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Receptor alfa de Estrógeno/fisiología , Receptores de Estrógenos/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Receptor alfa de Estrógeno/genética , Femenino , Regulación de la Expresión Génica , Células HeLa , Humanos , Células MCF-7 , Modelos Genéticos , Regiones Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Estrógenos/genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.
Asunto(s)
Envejecimiento/genética , Mitocondrias/metabolismo , Unión Neuromuscular/patología , Proteoma/análisis , Sarcopenia/patología , Transcriptoma , Envejecimiento/metabolismo , Animales , ADN Mitocondrial/genética , Metabolismo Energético , Perfilación de la Expresión Génica , Inmunohistoquímica , Modelos Lineales , Masculino , Análisis por Micromatrices , Mitocondrias/genética , Mitocondrias/patología , Fuerza Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Unión Neuromuscular/genética , Unión Neuromuscular/metabolismo , Cambios Post Mortem , Proteómica , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Regulación hacia ArribaRESUMEN
Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.