Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
2.
Clin Cancer Res ; 25(4): 1174-1184, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30333224

RESUMO

PURPOSE: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated. PATIENTS AND METHODS: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses. RESULTS: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 µmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity. CONCLUSIONS: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).


Assuntos
Janus Quinases/genética , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonas/administração & dosagem , Quinase Syk/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Receptores de Antígenos de Linfócitos B , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacocinética , Quinase Syk/genética , Microambiente Tumoral/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA