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1.
Acta Neuropathol ; 138(6): 1053-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31428936

RESUMO

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

2.
Front Oncol ; 8: 127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755954

RESUMO

Background and objective: Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy). Methods: Nine patients with newly diagnosed DIPG met enrollment criteria. Autologous dendritic cell vaccines (ADCV) were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received three boosts of tumor lysate every 3 months during the maintenance phase. Results: Vaccine fabrication was feasible in all patients included in the study. Non-specific KLH (9/9 patients) and specific (8/9 patients) antitumor response was identified by immunologic studies in peripheral blood mononuclear cells (PBMC). Immunological responses were also confirmed in the T lymphocytes isolated from the cerebrospinal fluid (CSF) of two patients. Vaccine administration resulted safe in all patients treated with this schema. Conclusion: These preliminary results demonstrate that ADCV preparation is feasible, safe, and generate a DIPG-specific immune response detected in PBMC and CSF. This strategy shows a promising backbone for future schemas of combination IT.

3.
Curr Cancer Drug Targets ; 18(1): 57-64, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28176655

RESUMO

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages -not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the "classic" current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the "classic boxes" heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to "risk-group" stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/prevenção & controle , Epigênese Genética , Adolescente , Neoplasias Encefálicas/patologia , Criança , Metilação de DNA , Gerenciamento Clínico , Regulação Neoplásica da Expressão Gênica , Humanos
4.
Target Oncol ; 7(3): 199-210, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22968692

RESUMO

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that affects a number of biological and biochemical functions through normal ligand-dependent signaling. It has oncogenic functions in a number of tumors including non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma, and neuroblastoma when altered by translocation or amplification or mutation. On August 2011, a small molecule inhibitor against ALK, crizotinib, was approved for therapy against NSCLC with ALK translocations. As we determine the molecular heterogeneity of tumors, the potential of ALK as a relevant therapeutic target in a number of malignancies has become apparent. This review will discuss some of the tumor types with oncogenic ALK alterations. The activity and unique toxicities of crizotinib are described, along with potential mechanisms of resistance and new therapies beyond crizotinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Crizotinibe , Resistencia a Medicamentos Antineoplásicos , Humanos , Modelos Genéticos , Mutação , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Transdução de Sinais , Translocação Genética
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