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

• Grant number: 19/06597-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2020
• Effective date (End): December 31, 2023
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Pablo Agustin Vargas
• Grantee: Luan César da Silva
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
• Associated research grant: 16/05710-4 - Disrupting tumor resistance through therapy targeting depletion of cancer stem cells in head and neck cancer, AP.TEM
• Associated scholarship(s): 21/13381-9 - Using small molecule libraries and high throughput screening to identify new inhibitory compounds to manage mucoepidermoid carcinomas from the salivary glands, BE.EP.DR

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, LUAN CESAR; FAUSTINO, ISABEL SCHAUSLTZ PEREIRA; CANTADORI, GABRIELA ROSSI; SANTOS-SILVA, ALAN ROGER; VARGAS, PABLO AGUSTIN; LOPES, MARCIO AJUDARTE. Adenocarcinoma not otherwise specified (NOS) arising in the sublingual gland: Rare case report and follow-up. Oral Oncology, v. 126, p. 3-pg., 2022-03-01. (19/06597-5)

SILVA, LUAN CESAR; BORGATO, GABRIELL BONIFACIO; WAGNER, VIVIAN PETERSEN; MARTINS, MANOELA DOMINGUES; SANTOS-SILVA, ALAN ROGER; DE CASTRO JR, GILBERTO; KOWALSKI, LUIZ PAULO; SQUARIZE, CRISTIANE HELENA; VARGAS, PABLO AGUSTIN; CASTILHO, ROGERIO MORAES. Repurposing NF kappa B and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas. AMERICAN JOURNAL OF CANCER RESEARCH, v. 13, n. 4, p. 13-pg., 2023-01-01. (19/06597-5, 16/05710-4)

SILVA, LUAN CESAR; BORGATO, GABRIELL BONIFACIO; WAGNER, VIVIAN PETERSEN; MARTINS, MANOELA DOMINGUES; ROCHA, GUILHERME ZWEIG; LOPES, MARCIO AJUDARTE; SANTOS-SILVA, ALAN ROGER; DE CASTRO JUNIOR, GILBERTO; KOWALSKI, LUIZ PAULO; NOR, JACQUES E.; et al. Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells. JOURNAL OF ORAL PATHOLOGY & MEDICINE, OCT 2021. (19/06597-5, 16/05710-4, 16/21785-4)