Disrupting tumor resistance through therapy targeting depletion of cancer stem cel...
Abstract
Head and Neck Squamous Cell Carcinomas (HNSCCs) represent one of the 6 most common Cancers worldwide. Among different therapeutic approaches, the use of chemotherapy alone or in association with radiotherapy or surgery has proven beneficial to the overall patient survival. Nonetheless, when compared to other Cancers like Leukemia and Hodgkin's disease, the benefits of chemotherapy for Head and Neck Cancer patients remain limited, mainly due to the development of chemoresistance. We have shown that the development of tumor resistance phenotype is mainly driven by (i) epigenetic modifications (e.g.: histone acetylation); (ii) activation of the NFkB signaling; (iii) and the presence of Cancer Stem Cells (CSCs). Our previous findings indicate that the activation of the NFkB signaling pathway is mediated by the deacetylation of tumor histones and the enrichment of the population of CSCs. Further, we found that pharmacological acetylation of tumor histones result in the depletion of CSCs. Once that histone acetylation regulates gene transcription related to the maintenance of CSCs and NFkB signaling, we propose the development of a new therapeutic approach for HNSCC using histone deacetylase inhibitors (HDACi) (Epi-drugs) in combination with pharmacological inhibition of IkB± phosphorylation (NFkB super-repressor). We anticipate that our novel therapeutic approach will disrupt the tumor resistance to cisplatin, the most common chemotherapeutic agent used in the treatment of HNSCC. Of note, targeted inhibition of IkB± phosphorylation results in selective down-regulation of NFkB independently from the off-target effects observed during administration of the NFkB inhibitors Bortezomib and Velcade. Our approach proposes the use of low doses of Emetine; an FDA-approved drug used in the treatment of amoebiasis. This proposal encompasses the collaboration of the University of Campinas (UNICAMP), The Federal University of Rio Grande do Sul (UFRGS), and the University of Michigan (UMICH), and is divided into 3 aims. First aim will (i) determine the therapeutic efficacy of HDAC and IkB± inhibition in the depletion of CSCs and sensitization of HNSCC cell lines to cisplatin; (ii) therapeutic efficiency of HDACi (SAHA®) and IkB± inhibitor (Emetine®) in HNSCC xenografts following by ChIP Seq analysis; (iii) construction of TMAs using PDX tumor samples treated with SAHA® and Emetine® following by the characterization of the epigenetic profile of tumors. Altogether, our proposal will investigate unknown issues associated with the epigenetic control of CSCs, along the validation of a novel therapeutic approach to reduce chemoresistance of HNSCC. (AU)