Disrupting tumor resistance through therapy targeting depletion of cancer stem cells in Salivary Mucoepidermoid Carcinomas

Abstract

Salivary Mucoepidermoid Carcinoma (MEC) has a variable biological behavior, with tumor grade and stage of disease being the most important factors for prognosis. Low-grade and small-sized tumors without lymph node involvement present disease-free survival and favorable prognosis, while the opposite is seen in tumors of a high degree of differentiation and advanced stage. In this sense, the treatment for MEC follows without much progress. The proposed radio and chemotherapeutic regimens are poorly reproduced due to the toxicities brought on by radiotherapy and the resistance against the current chemotherapeutic agents, mainly found by Cancer Stem Cells (CSCs). Resistance to these current regimens may occur due to the intense compaction (hypoacetylation) of the CSCs chromatin that can be induced by the activation of nuclear transcription factor kappa B (NFκB) by the phosphorylation of IκBα). Therefore, we propose in this Ph.D. project to evaluate in vitro the effect of inhibitors of histone deacetylase (iHDAC) and phosphorylation of IκBαisolated and associated with Cisplatin in the treatment of MEC characterizing the population of CSCs. For this, cells derived from MEC will be treated with Emetine (inhibitor of IκBα), Vorinostat (iHDAC) and Cisplatin alone and associated in different combinations. The outcomes of the therapies will be evaluated by means of flow cytometry, ball formation assays for the detection of CSCs. Analyzes of the epigenetic profile of CSCs will also be performed through immunofluorescence. We hope that this study proposes a new systemic therapeutic strategy for patients with MEC that aims to act in particular in CSCs, trying to minimize the chances of recurrence and tumor metastasis. (AU)