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
Assunto da revista
Intervalo de ano de publicação
1.
EMBO Mol Med ; 12(6): e10979, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32419365

RESUMO

Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti-tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term "immunogenic cell death" is not fully defined, activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre-clinical application of an in vivo treatment protocol for soft-tissue sarcoma that directly engages RIPK1-mediated immunogenic cell death. We find that RIPK1-mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1-induced cell death in patients with advanced disease at limb extremities.


Assuntos
Morte Celular Imunogênica , Sarcoma , Apoptose , Linfócitos T CD8-Positivos/metabolismo , Humanos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sarcoma/terapia , Transdução de Sinais , Fator de Necrose Tumoral alfa
2.
J Invest Dermatol ; 134(10): 2630-2638, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24662767

RESUMO

Cutaneous SCC (cSCC) is the most frequently occuring skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here, we use massively parallel exome and targeted level sequencing of 132 sporadic cSCCs and of 39 squamoproliferative lesions and cSCCs arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples, to identify NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib-induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC, suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCCs, and regions of NOTCH1 loss or downregulation are frequently observed in normal-looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Mutação/genética , Receptor Notch1/genética , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor Notch1/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Pele/metabolismo , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo , Dermatopatias/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Sulfonamidas/uso terapêutico , Vemurafenib
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA