American Head & Neck Society
Translational Research Meeting

April 21-22, 2015

AHNS Annual Meeting
April 22-23, 2015 during the
Combined Otolaryngology Spring Meetings

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Mgmt Hypermethylation As A Promising Marker For Ast1306 Therapy Response

Presentation: S006
Topic: Epigenetics in Cancer
Type: TRM
Date: Tuesday, April 21, 2015
Session: 11:00 am - 12:30 pm
Authors: Lidia M R B Arantes, PhD, Renato J S Oliveira, MsC, Ana Carolina de Carvalho, PhD, Matias E Melendez, PhD, Rui M Reis, PhD, André L Carvalho, MD, PhD
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Institution(s): Molecular Oncology Research Center, Barretos Cancer Hospital – Pio XII, Barretos – SP, Brazil
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Background: Over the last years, diagnosis and management of head and neck cancer (HNSCC) patients have improved through combined efforts in surgery, radiotherapy and chemotherapy, but long-term survival rates have improved only marginally, and the overall 5-year survival rate is around 50%. Late diagnosis and frequent loco-regional recurrences are the major causes for the poor prognosis. Therapies targeting inhibition of multiple points along signal transduction pathways are potential new approaches in the treatment of cancer. Overexpression of epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase growth factor receptor, is found in more than 90% of HNSCC tumors and anti-EGFR therapy has shown to be effective against HNSCC. AST1306 is a novel anilino-quinazoline compound, which irreversibly inhibits the enzymatic activities of wild-type EGFR. Hypermethylation in the promoter regions of genes is associated with suppression of gene expression and has been considered a potential molecular marker for several tumor types, including HNSCC. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA-repair protein that protects glioblastoma tumor cells against alkylating agents including temozolomide (TMZ) by removing alkyl adducts from the O6-position of guanine. Several studies have demonstrated that epigenetic silencing of MGMT gene by promoter methylation was of predictive significance for prolonged survival to the combination of TMZ and radiotherapy in glioblastoma patients.

Objectives: To evaluate the methylation status of DCC, MGMT and p16 genes in HNSCC cell lines and associate the molecular findings with the response profile to AST1306.

Materials and Methods: Six HNSCC cell lines and A431 (control) were used to test the treatment efficacy of AST1306 by cell viability assays (MTS). Cells were seeded in 96 well plates, exposed to increasing doses of AST1306 (0 - 2.5 µM) for 72 hours. The methylation profile of DCC, MGMT and p16 genes was assessed by Pyrosequencing in a PSQ96ID pyrosequencer.

Results: To quantify the response to AST1306, according to the methylation status of DCC, MGMT and p16, areas under the curve (AUCs) were calculated for all cell lines. Interestingly, the MGMT hypermethylation status showed the highest level of sensitivity and specificity (AUC=1.000) in discriminating sensitive from resistant HNSCC cell lines to AST1306. The AUC levels for the other genes were 0.500 for DCC and 0.542 for p16.   

Conclusion: MGMT hypermethylation in HNSCC cell lines predicts response to AST1306, irrespective of HPV status, showing its feasibility as a marker that can potentially be used in a clinical setting.

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