Disrupting tumor resistance through therapy targeting depletion of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma patient-derived xenograft

Abstract

Head and Neck Squamous Cell Carcinomas (HNSCCs) are the sixth most common Cancer worldwide, with the mouth and oropharynx as the most affected sites. The treatment is complex and involves, in most cases, the use of multiple therapeutic modalities in combination. Chemotherapy, with or without surgery or radiotherapy, has been widely used in advanced cases of HNSCC. However, when compared to other types of Cancer, the treatment response is limited and the main reason of this limitation is based on tumor resistance to chemotherapeutic agents. Resistance to these agents may occur due to intense compaction (hypoacetylation) of chromatin in Cancer Stem Cells (CSCs) and to its accumulation, which can be induced by activation of nuclear Transcription Factor kappa B (NFºB) through phosphorylation of IºB±. It has already been shown that pharmacological acetylation of histones induces a reduction in the number of CSCs. Therefore, the aim of this project is to assess in vivo the effect of Histone Deacetylase inhibitors (HDACi) and selective inhibitors of IºB± phosphorylation (IºB±i; NFºB super repressor) isolated and associated with Cisplatin in the treatment of HNSCC. For this purpose, Tongue Squamous Cell Carcinoma Xenografts from patients and implanted in the dorsum of Nude mice will be submitted to different therapeutic protocols with SAHA (HDACi), Cephalin (IºB±i) and Cisplatin. The outcomes of the therapies will be evaluated through clinical evaluation of the tumors, flow cytometry and mapping of the epigenetic profile of HNSCC (ChIP-seq). We aim to propose a new therapeutic strategy that leads to the clinical reduction of HNSCC, in order to minimize the chances of tumor recurrence and metastases. (AU)