Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers

Author(s):Show less -

Mak, Milena Perez ^[1] ; Pasini, Fatima Solange ^[2] ; Diao, Lixia ^[3] ; Teixeira Garcia, Fabyane O. ^[2] ; Takahashi, Tiago Kenji ^[1] ; Nakazoto, Denyei ^[1] ; Martins, Renata Eiras ^[1] ; Almeida, Cristiane Maria ^[1] ; Vamondes Kulcsar, Marco Aurelio ^[4] ; Lamounier, Valdelania Aparecida ^[1] ; Nunes, Emily Montosa ^[2] ; de Souza, Isabela Cristina ^[2] ; Taveira Garcia, Marcio Ricardo ^[5] ; Amadio, Alex Vieira ^[1] ; Siqueira, Sheila Aparecida C. ^[6] ; Longo Snitcovsky, Igor Moyses ^[2] ; Sichero, Laura ^[2] ; Wang, Jing ^[4] ; de Castro Jr, Gilberto

Affiliation

^[1] Univ Sao Paulo, Dept Med Oncol, Inst Canc Estado Sao Paulo, Hosp Clin, Fac Med, Av Dr Arnaldo, 251 12th Floor, BR-01246000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Ctr Translat Invest Oncol, Inst Canc Estado Sao Paulo, Hosp Clin, Fac Med, Av Dr Arnaldo, 251 12th Floor, BR-01246000 Sao Paulo, SP - Brazil

^[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, 1400 Pressler St Floor 4, FCT4-6000, Houston, TX 77030 - USA

^[4] Univ Sao Paulo, Head & Neck Surg Dept, Inst Canc Estado Sao Paulo, Hosp Clin, Fac Med, Av Dr Arnaldo, 251 12th Floor, BR-01246000 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Dept Radiol, Inst Canc Estado Sao Paulo, Hosp Clin, Fac Med, Av Dr Arnaldo, 251 12th Floor, BR-01246000 Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Dept Pathol, Hosp Clin, Fac Med, Av Dr Eneas Carvalho Aguiar 255, BR-05403000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: ECANCERMEDICALSCIENCE; v. 14, DEC 15 2020.
• Web of Science Citations: 0

Abstract

Background: Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers. Methods: This phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated. Results: Given significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41-65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival. Conclusions: VPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122). (AU)

• FAPESP's process: 15/01584-1 - HDAC2 and HR23B expression in the primary tumor and modulation of histone acetylation status in peripheral mononuclear cells in patients with oral and oropharyngeal squamous cell carcinoma under chemoradiation and valproic acid
• Grantee: Alex Vitorio Amadio
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/26965-5 - Valproic Acid and Platinum-based Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma
• Grantee: Gilberto de Castro Junior
• Support type: Regular Research Grants