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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2019.tde-09122019-120313
Document
Author
Full name
Milena Perez Mak
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Castro Junior, Gilberto de (President)
Lima, Carmen Silvia Passos
Colli, Leandro Machado
Folgueira, Maria Aparecida Azevedo Koike
Title in Portuguese
Avaliação da eficácia de ácido valproico combinado ao tratamento padrão de quimiorradioterapia concomitante baseada em cisplatina, em pacientes portadores de carcinoma epidermoide de cabeça e pescoço localmente avançado
Keywords in Portuguese
Ácido valproico
Estudo de fase II
MicroRNAs
Neoplasias de cabeça e pescoço
Quimiorradioterapia
Regulação epigenética
Abstract in Portuguese
Introdução: O tratamento padrão do carcinoma epidermoide de cabeça e pescoço (CECP) localmente avançados (LA) irressecável é a quimiorradioterapia (QRT) baseada em cisplatina. O ácido valproico (VPA) atua como regulador epigenético através da inibição da deacetilação das histonas e apresenta ação radiossensibilizante in vitro. O objetivo do presente estudo foi avaliar a eficácia da associação de VPA a QRT e biomarcadores associados em pacientes portadores de CECP-LA candidatos à quimiorradioterapia baseada em cisplatina. Materiais e métodos: Estudo de fase II segundo desenho de Simon para avaliação da taxa de reposta (TR) radiológica após 8 semanas do término da QRT combinada ao VPA (P3). Coletou-se amostras para avaliação de perfil de microRNAs (saliva e plasma) pré-tratamento (P0), após 2 semanas de VPA (P1) e em P3, e acetilação de histonas (plasma) em P0, P1 e no término da QRT com VPA (P2). A expressão imuno-histoquímica de p16, HDAC2 e HR23B foi avaliada nos tumores. Os microRNAs (miRs) escolhidos a partir do perfil em plasma, foram validados por qPCR na saliva e estudos funcionais com vesículas extracelulares foram conduzidos. Resultados: Dez pacientes masculinos, tabagistas atuais ou passados, idade mediana de 55 anos (41-65) com tumores de orofaringe irressecáveis (p16 negativos) foram incluídos e tratados. O recrutamento foi suspenso devido a toxicidade excessiva. Em nove pacientes avaliáveis observou-se uma TR de 88%. Um escore H superior a 170 de expressão de HDAC2 apresentou 90% de acurácia em predizer a sobrevida livre de doença em 6 meses. Pacientes e voluntários sadios apresentaram perfis de microRNAs (miRs) distintos, com 169 miRs diferencialmente expressos, considerando false discovery rate de 5%. miRs supressores tumorais como miR-31, -222, -let-7a/b/e e -145 encontravam-se hipoexpressos em pacientes em comparação a voluntários sadios. Menores níveis de miR-let-7a/e em pacientes comparados a voluntários sadios foram validados em saliva com qPCR. Houve aumento da migração celular com acréscimo de vesículas extracelulares de pacientes não respondedores em comparação ao controle. Conclusões: A combinação de VPA a QRT mostrou sinais de eficácia, porém com toxicidades limitantes. Caracterizou-se um distinto padrão de expressão de miRs entre pacientes e voluntários sadios, sendo validados menores níveis de miR-let-7a/e em saliva
Title in English
Phase II trial of valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (pts)
Keywords in English
Chemoradiotherapy
Epigenetics
Head and neck neoplasms
MicroRNAs
Phase II trial
Valproic acid
Abstract in English
Background: Although cisplatin-based chemoradiation (CRT) offers LA HNSCC pts a high local control rate, relapses are frequent. Our goal was to evaluate whether valproic acid (VA), a histone deacetylase inhibitor (HDACi), combined with CRT in LA HNSCC improved response rate (RR) and associated biomarkers. Methods: This phase II trial included patients with unresectable oropharynx (OP) and oral cavity LA HNSCC. CRT begun after two weeks of VA (P1). RR at 8 weeks after CRT+VA (P2) by response evaluation criteria in solid tumors (RECIST) version 1.1. was our primary goal. Biomarkers included microRNA (miR) PCR-array profiling in plasma samples at baseline, P1 and P2, which were compared to healthy controls by two-sample t-test for each miR. Distribution of the p-values was analyzed by beta-uniform mixture. Findings were validated by real-time polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. Functional extracellular vesicles (EV) assays were performed in head and neck cell lines (SCC9 and SCC25). p16, HDAC2 and HR23B tumor immunohistochemistry were also evaluated. Results: We included 10 LA p16 negative OP pts. Median age was 55 years (41-65). All pts were male, smokers/ex-smokers and with previous moderate/high alcohol intake. Due to significant toxicities, accrual was terminated. In nine evaluable patients, a RR of 88% was observed. miR plasma profiling revealed differential expression of 169 miRs between pts and controls (FDR 0.05), including lower expression of known tumor suppressors (TS) such as miR-31, -222, -let-7a/b/e and -145. There were no significant differences in miR expression at P1 versus baseline. P2 compared to baseline had lower levels of miR-31, in particular in responders (p 0.007). miR-let-7a/e lower expression in pts compared to healthy volunteers (HV) was validated in saliva qPCR. EVs from HV, baseline responders and non-responders and pts at P2 did not alter cell lines sensitivity to cisplatin, however increased migration. A HDAC2 H-score above 170 was 90% accurate in predicting six-month disease-free survival. Conclusions: VA+CRT improved RR compared to our historical control; however, at the cost of prohibitive toxicities, which prevented the trial from continuing. Pts and HV had a markedly different pattern of miR expression, mainly with low levels of TS targeting TP53. miR-let-7a/e levels were lower in pts compared to healthy controls, reinforcing the aggressive nature of such tumors
 
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Publishing Date
2019-12-09
 
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