Abstract 4058: Preclinical and phase-2 clinical study of valproic acid administered in combination with cisplatin and cetuximab in recurrent/metastatic head and neck cancer
Authors: Alfredo Budillon, Andrea I. Zotti, Carlo Vitagliano, Elena Di Gennaro, Francesco Caponigro
Journal: Cancer Research (2017)

Abstract Recurrent metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a devastating malignancy with a poor prognosis and the combination of cisplatin (CDDP) and cetuximab (CX) is one of the gold standard for treatment. However, this therapy is often associated with high toxicity and resistance, suggesting that the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including CDDP and anti-Epidermal Growth Factor Receptor (EGFR) compounds. EGFR overexpression is involved in chemotherapy resistance and recently it has been demonstrated that EGFR nuclear localization represents one of the mechanism of resistance to both CDDP and CX. Our group have demonstrated that HDACi synergize with anti-EGFR agents by modulating ErbB receptors expression including EGFR. In this study we evaluated the capability of Valproic acid (VPA), a generic low-cost anticonvulsivant drug with HDACi activity, to enhance the efficacy of CDDP-CX association in SCCHN cells with different EGFR basal expression and genetic backgrounds. We showed, by the calculation of combination indexes, an antiproliferative synergistic interaction between equipotent doses of VPA and CDDP-CX in CAL27 and FaDu SCCHIN cells using either simultaneous or sequential (with 24 h delay) schedule of administration. Notably, this effect was not observed in immortalized human fibroblasts BJ-hTERT, suggesting a selective effect toward tumor cells. Next, we confirmed synergistic interaction by testing clinically achievable concentrations of VPA/ CDDP-CX combination also on CAL27 and FaDu 3D spheroid cultures, showing inhibition of first- and second-generation spheroids formation by triple combination, compared to single agent treatments. Moreover we demonstrated that VPA was able to down-regulate EGFR and to prevent EGFR nuclear translocation induced by CDDP and CCDDP/CX combination, thus preventing the activation of DNA repair and survival pathways. Indeed, we showed that VPA was able to increase DNA damage and apoptosis induced by CDDP-CX combination, evaluated by gamma H2AX foci and annexin V-FITC assay, respectively. In vivo preclinical study is currently ongoing. All together these data represent the rationale of the ongoing V-CHANCE phase-2 clinical trial evaluating VPA/ CDDP-CX combination in R/M SCCHN patients. We are also currently investigating pharmacodynamics/predictive biomarkers of treatment efficacy/resistance on patient’s samples. Citation Format: Alfredo Budillon, Andrea I. Zotti, Carlo Vitagliano, Elena Di Gennaro, Francesco Caponigro. Preclinical and phase-2 clinical study of valproic acid administered in combination with cisplatin and cetuximab in recurrent/metastatic head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4058. doi:10.1158/1538-7445.AM2017-4058