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.

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

“…Genetic and epigenetic alterations modulate the hyperactivation of oncogenic signalling transduction and are associated with the pathogenesis of glioblastomas. The upstream oncogenic kinases trigger downstream transcription factor‐regulated oncogene expression, promoting the progression of glioblastomas . The blockage of oncogenic signalling transduction contributes to the inhibition of tumour progression.…”

The Emerging Roles of RNA Modifications in Glioblastoma

“…Therefore, it is urgent to develop new therapeutic strategies to treat GBM; however, the natural characteristics of GBM remain not fully understood.To know how GBM initiates and develops, the molecular characteristics of GBM should be accurately determined. Actually, many genetic, epigenetic, metabolic and immunologic profiles in GBM have been described in recent years [5][6][7][8][9]. These landscapes of GBM have greatly expanded our knowledge about GBM, thereby providing clues for the treatment of this disease.…”

Improving drug discovery using image-based multiparametric analysis of epigenetic landscape

“…7a). To test whether these differences are biologically meaningful, we correlated MIEL-based activity of epigenetic drugs which are often designed to work in combination with other treatments (16,17). One common approach is to use epigenetic drugs to sensitize tumor cells to a standard of care in cytotoxic treatment (15,(43)(44)(45), such as radiation and temozolomide (TMZ), which are used to treat glioblastoma.…”

“…Multiple approaches aimed at reducing or circumventing the resilience of TPCs have been proposed. These include targeting epigenetic enzymes (i.e., enzymes that write, remove, or read DNA and histone modifications) that would increase sensitivity to cytotoxic treatments (14)(15)(16)(17), differentiating TPCs to reduce tumor expansion by decreased cell proliferation, and increasing sensitivity to cytotoxic treatments (18)(19)(20)(21)(22)(23).…”