Epigenetic targeting of glioblastoma

Abstract

Glioblastoma is one of the first tumors where the biological changes accompanying a single epigenetic modification, the methylation of the MGMT gene, were found to be of clinical relevance. The exploration of the epigenomic landscape of glioblastoma has allowed to identify patients carrying a diffuse hypermethylation at gene promoters and with better outcome. Epigenetic and genetic data have led to the definition of major subgroups of glioma and were the basis of the current WHO classification of CNS tumors and of a novel classification based solely on DNA methylation data that shows a remarkable diagnostic precision. The reversibility of epigenetic modifications is considered a therapeutic opportunity in many tumors also because these alterations have been mechanistically linked to the biological characteristics of glioblastoma. Several alterations like IDH1/2 mutations that interfere with "epigenetic modifier" enzymes, the mutations of the histone 3 variants H3.1 and H3.3 that alter the global H3K27me3 levels and the altered expression of histone methyltransferases and demethylases are considered potentially druggable targets in glioma and molecules targeting these alterations are being tested in preclinical and clinical trials. The recent advances on the knowledge of the players of the "epigenetic orchestra" and of their mutual interactions are indicating new paths that may eventually open new therapeutic options for this invariably lethal cancer. This study was supported by the Italian Ministry of Health, Core Grant Ricerca Corrente to the IRCCS Ospedale Policlinico San Martino, by the grant from the Fondazione Compagnia di San Paolo-Torino: Terapie innovative per il glioblastoma and by the grant Associazione Italiana Ricerca sul Cancro (AIRC) 5 × 1000 N. 21073: Epigenetic modeling/remodeling of cancer metastases and tumor immune contexture to improve efficacy of immunotherapy.