RESUMO
Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Linfoma Anaplásico de Células Grandes/genética , NF-kappa B/metabolismo , Receptores Proteína Tirosina Quinases/genética , Fator 1 Associado a Receptor de TNF/genética , Translocação Genética/genética , Quinase do Linfoma Anaplásico , Animais , Western Blotting , Citometria de Fluxo , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoprecipitação , Hibridização in Situ Fluorescente , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/mortalidade , Camundongos , Camundongos Endogâmicos NOD , NF-kappa B/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo , Inibidores de Proteassoma/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fator 1 Associado a Receptor de TNF/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inappropriate expression or activation of transcription factors can drive patterns of gene expression, leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we used chromatin immunoprecipitation followed by deep sequencing to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared with B-cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a signal transducer and activator of transcription3 inhibitor provided enhanced cell killing in triple-negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Amplificação de Genes , Peptidomiméticos/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/metabolismo , Sinergismo Farmacológico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-6 , Pirrolidinas/farmacologia , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Many of those involved in palliative care have justifiable objections to the introduction of intravenous hydration in patients with dehydration-associated symptoms and advanced cancer. Researchers from the University of Buenos Aires carried out a randomized, comparative and prospective trail to determine the usefulness of hypodermoclysis in the control of thirst, chronic nausea and delirium. Forty-two patients were randomized into two groups. Both groups received drugs subcutaneously (haloperidol 2.5 mg every 4 hours to control delirium and/or metoclopramide 10 mg every 4 hours to control chronic nausea). The study group also received 1000 ml 5% dextrose in water infusion plus 140 milliequivalent per litre (mEq/L) sodium chloride, at a rate of 42 ml/hour per day. Both groups showed significant and equal improvements in relief of thirst and chronic nausea at 24 hours. After 48 hours, this improvement was maintained in the group that received hydration, but only for the relief of chronic nausea. Delirium did not improve significantly in either group during the 48-hour trial period. Current data suggest that decisions on rehydration of patients with terminal-phase cancer should be based more on the patient's comfort than on providing optimal hydration.
