Abstract 55: SET protein as a therapeutic target in head and neck squamous cell carcinoma

Abstract

Abstract Introduction: The study of cancer molecular profiles allowed the development of several targeting agents, such as OP449 and FTY720/Fingolimod drugs, that can act as PP2A activators. OP449 is a synthetic peptide with antineoplastic action and FTY720 is a potent inhibitor of tumor growth and angiogenesis. SET/I2PP2A, a multifunctional protein, is a potent and specific inhibitor of PP2A and is upregulated in head and neck squamous cell carcinoma (HNSCC). SET has been proposed to be an oxidative stress sensor, promoting cell survival and apoptosis. Both OP449 and FTY720 bind to SET and destabilize SET/PP2A complex, reactivating the PP2A function. Objectives: The aim was to evaluate the antitumoral effect, in vitro and in vivo, of the association OP449 plus FTY720, in HNSCC. Material and Methods: HNSCC lineages were analyzed for SET protein status by Western blotting and for cancer stem cell population by using aldehyde dehydrogenase 1 (ALDH1) activity assay. Alterations in SET targets were confirmed by Western blotting. The cytotoxic effects of OP449 and/or FTY720, under different concentrations, were determined after 72 hours through the resazurin assay. The coefficient of drug interaction (CDI) was used to analyze the synergistic inhibitory effect of drug combination. Xenograft tumor model in Balb/c nude mice (n=5 per group), by subcutaneous injection of cells into the flank of the mouse, was used to investigate the antitumoral potential of treatment with OP449 and/or FTY720, every 48 h, for 15 days. Results and Discussion: HN12 cells were selected due to the higher levels of SET and higher ALDH1 activity compared to other HNSCC cells. The treatment of HN12 cells with OP449 altered the levels of SET targets. A significant synergistic effect was observed when cells were pre-treated with 2 μM OP449 followed by 15 μM FTY720 (CDI=0.27 ± 0.088). Nude mice bearing HN12 human xenograft tumors treated with OP449 (5 mg/kg) and/or FTY720 (2 mg/kg) showed reduction in tumor growth compared to either control (vehicle) or compounds isolated. Conclusion: Our results indicate that OP449 and FTY720 have a synergistic antitumoral effect, opening perspectives for either alternating or combined therapies in HNSCC, having SET protein as a target. Financial support: FAPESP, CNPq and CAPES. Citation Format: Renata Nishida Goto, Karina Stringhetta-Padovani, Michael Vitek, Carlos Curti, Andreia Machado Leopoldino. SET protein as a therapeutic target in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 55.