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1.
Acta Neuropathol ; 128(4): 561-71, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25008768

RESUMO

The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.


Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Glioma/classificação , Glioma/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Ilhas de CpG/genética , DNA Helicases/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Alemanha , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Nucleares/genética , Telomerase/genética , Proteínas Supressoras de Tumor/genética , Proteína Nuclear Ligada ao X
2.
Hum Gene Ther ; 25(7): 631-41, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24635742

RESUMO

Standard integration-proficient lentiviral vectors (IPLVs) are effective at much lower doses than other vector systems and have shown promise for gene therapy of Parkinson's disease (PD). Their main drawback is the risk of insertional mutagenesis. The novel biosafety-enhanced integration-deficient lentiviral vectors (IDLVs) may offer a significant enhancement in biosafety, but have not been previously tested in a model of a major disease. We have assessed biosafety and transduction efficiency of IDLVs in a rat model of PD, using IPLVs as a reference. Genomic insertion of lentivectors injected into the lesioned striatum was studied by linear amplification-mediated polymerase chain reaction (PCR), followed by deep sequencing and insertion site analysis, demonstrating lack of significant IDLV integration. Reporter gene expression studies showed efficient, long-lived, and transcriptionally targeted expression from IDLVs injected ahead of lesioning in the rat striatum, although at somewhat lower expression levels than from IPLVs. Transgenic human glial cell line-derived neurotrophic factor (hGDNF) expression from IDLVs was used for a long-term investigation of lentivector-mediated, transcriptionally targeted neuroprotection in this PD rat model. Vectors were injected before striatal lesioning, and the results showed improvements in nigral dopaminergic neuron survival and behavioral tests regardless of lentiviral integration proficiency, although they confirmed lower expression levels of hGDNF from IDLVs. These data demonstrate the effectiveness of IDLVs in a model of a major disease and indicate that these vectors could provide long-term PD treatment at low dose, combining efficacy and biosafety for targeted central nervous system applications.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Terapia Genética/métodos , Vetores Genéticos , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Lentivirus , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/terapia , Animais , Sobrevivência Celular/genética , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley
3.
Clin Cancer Res ; 20(24): 6304-13, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25338498

RESUMO

PURPOSE: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma. EXPERIMENTAL DESIGN: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. RESULTS: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1-19.6] for rRT and 20.7% (95% CI, 11.2-33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3-3.8) months and 4.5 (95% CI, 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27-0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36-1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06-0.58) for treatment with APG101, suggesting a potential biomarker. CONCLUSIONS: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptor fas/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores , Terapia Combinada , Esquema de Medicação , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem , Receptor fas/administração & dosagem , Receptor fas/efeitos adversos
4.
Neuro Oncol ; 15(8): 1017-26, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23595628

RESUMO

BACKGROUND: The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients. METHODS: Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial. RESULTS: IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival. CONCLUSIONS: Despite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.


Assuntos
Astrocitoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Metilação de DNA , Glioblastoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Astrocitoma/mortalidade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Glioblastoma/genética , Glioblastoma/mortalidade , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores , Fenótipo , Prognóstico , Regiões Promotoras Genéticas/genética , Taxa de Sobrevida , Adulto Jovem
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