Advancements in systemic therapy targeting depletion of mucoepidermoid carcinoma cancer stem cells by the epigenetic drugs management

Author(s)

Luan César da Silva

• Document type: Doctoral Thesis
• Press: Piracicaba, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba (FOP)
• Defense date: 2023-12-04

Examining board members

Pablo Agustin Vargas; Cristiane Helena Squarize; Gabriell Bonifácio Borgato; Vivian Petersen Wagner; Manoela Domingues Martins

• Advisor: Rogério Moraes de Castilho; Pablo Agustin Vargas

Abstract

Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland tumor. The current treatment for MEC is surgical excision, and the development of highly effective systemic strategies for MEC remains a challenge. There are few systemic therapies targeting CME. Therefore, the present study aimed to evaluate the effect of different therapies using new drugs and drug repurposing in MEC cell lines. Firstly, an overview was carried out to integrate and summarize studies from existing clinical trials that evaluated the use of systemic therapies for the treatment of salivary gland carcinomas. We observed that despite all advances, there is still no effective evidence-based systemic therapy regimen defined for the treatment of salivary gland carcinomas, where all identified clinical trials showed low rates of complete and partial responses. Together, two in vitro studies were developed, in which the first evaluated the potential use of cephaeline as a therapeutic strategy for MEC management, and the second investigated the effects of the NFkB inhibitor (emetine) and the histone deacetylase inhibitor (SAHA) in the biology of MEC cancer stem cells (CSCs), and we also evaluated whether this combined therapy would benefit the standard treatment consisting of the administration of cisplatin. The assays were performed using the UM-HMC1, UM-HMC2, and UM-HMC3A MEC cell lines. Cellular viability, migration, and proliferation were determined. Immunofluorescence staining for histone H3 lysine 9 (H3k9ac) and p65 (NFkB pathway effector) were performed. The presence of CSCs was assessed by the enzymatic activity of ALDH by flow cytometry, and through functional assays evaluating the formation of tumorpheres. The results demonstrated that cephaeline has antineoplastic properties in all MEC lines studied, regulating the viability, migration, and proliferation of tumor cells, and interrupting the ability of tumor cells to generate tumorpheres. Furthermore, our findings suggested that the administration of low concentrations of emetine and SAHA is more effective in disrupting MEC CSCs, whereas the administration of emetine in combination with cisplatin constitutes an effective therapy for targeting non-CSCs (AU)

• FAPESP's process: 19/06597-5 - Disrupting tumor resistance through therapy targeting depletion of cancer stem cells in Salivary Mucoepidermoid Carcinomas
• Grantee: Luan César da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate