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Doctoral Thesis
DOI
https://doi.org/10.11606/T.23.2020.tde-26022021-074653
Document
Author
Full name
Letícia Drumond de Abreu Guimarães
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Júnior, Décio dos Santos Pinto (President)
Castilho, Rogério Moraes de
Sedassari, Bruno Tavares
Sousa, Suzana Cantanhede Orsini Machado de
Title in Portuguese
Entinostat sensibiliza e potencializa o efeito terapêutico da Cisplatina em Carcinoma Adenoide Cístico de Glândulas Salivares: estudo em modelos de xenoenxerto derivado do paciente (PDX)
Keywords in Portuguese
Biomarcadores Tumorais
Carcinoma Adenoide Cístico
Epigenoma
Inibidores de Histona Desacetilases
Terapia Combinada
Tratamento com Drogras
Abstract in Portuguese
O Carcinoma Adenóide Cístico (CAC) de glândulas salivares é caracterizado por potencial de crescimento lento e metastático, muitas das vezes resistente à quimioterapia. Além disso, verificaram recentemente que NOTCH1 e MYB mutados são sugestivos de mau prognóstico. Por isso, o objetivo do presente estudo é verificar a eficiência de um novo inibidor de histona desacetilase (iHDAC), o Entinostat, em Pacientes Xenoenxertos Derivados (PDX) de CAC de glândulas salivares (ACCx9, ACC5M1, ACCx6). Os modelos PDX foram divididos em Controle, Entinostat, Cisplatina e Entinostat combinada a Cisplatina e a inibição do crescimento tumoral (ICT) foi calculada para cada amostras e todas foram processadas para expressão gênica usando Nanostring e marcadores principais usando imunohistoquímica/ imunofluorescência. Todos responderam à terapia combinada de Entinostat/Cisplatina e o ICT observado foi 106%, 63% e 38% para ACCx9, ACC5M1 e ACCx6, respectivamente. Além disso, descobrimos que os tumores que apresentaram melhor resposta à terapia apresentaram baixa expressão de Ki-67, p16ink4a, yH2AX, NFkB, p300, DNMT1 e regulação positiva da caspase3, H3K9, H4K5, H4K8, H4K12, H4K16 e acetil-p53. A expressão reduzida de NGF, NGFR e DLL1 foram associadas a uma melhor resposta à terapia, enquanto altos níveis de MYB, senescência celular e metilação de histonas foram associados a uma resposta reduzida. Portanto, Entinostat sensibiliza e potencializa o efeito terapêutico da Cisplatina no CAC de glândulas salivares inibindo genes associados às modificações de cromatina e ratifica ser uma terapia promissora, porém age de forma distinta devido a heterogeneidade fenotípica e morfológica do CAC.
Title in English
Entinostat sensitizes and potentiates the therapeutic effect of Cisplatin in Adenoid Cystic Carcinoma from Salivary Glands: study in patient-derived xenograft (PDX) models
Keywords in English
Adenoid Cystic Carcinoma
Combined Therapy
Drug Therapy
Epigenome
Histone Deacetylase Inhibitors
Tumor Biomarkers
Abstract in English
Adenoid Cystic Carcinoma (CAC) from salivary glands is characterized by slow-gowing and metastatic potential, often resistant to chemotherapy. In addition, they recently found that NOTCH1 and MYB mutated are suggestive of poor prognosis. Therefore, the aim of the present study is to verify the efficiency of a new histone deacetylase inhibitor (iHDAC), Entinostat, in Patients Derivative Xenografts (PDX) from salivary gland CAC (ACCx9, ACC5M1, ACCx6). The PDX models were divided into Control, Entinostat, Cisplatin and Entinostat combined with Cisplatin and tumor growth inhibition (TGI) was calculated for each samples and all were processed for gene expression using Nanostring and main markers using immunohistochemistry / immunofluorescence. All responded to the combined Entinostat / Cisplatin therapy and the observed TGI was 106%, 63% and 38% for ACCx9, ACC5M1 and ACCx6, respectively. Furthermore, we found that tumors presenting better response to therapy showed low expression of Ki-67, p16ink4a, yH2AX, NFkB, p300, DNMT1 and regulation of caspase3, H3K9, H4K5, H4K8, H4K12, H4K16 and acetyl-p53. The upreduced expression of NGF, NGFR and DLL1 were associated with a better response to therapy, while high levels of MYB, cellular senescence and histone methylation were associated with a reduced response. Therefore, Entinostat sensitizes and potentiates the therapeutic effect of Cisplatin in the CAC of salivary glands by inhibiting genes associated with chromatin modifications and confirms that it is a promising therapy but acts differently due to the phenotypic and morphological heterogeneity of CAC.
 
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Publishing Date
2022-01-19
 
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