Epigenetic Targeting of Glioblastoma.

Massimo Romani,Barbara Banelli,Maria Pia Pistillo

doi:10.3389/fonc.2018.00448

Massimo Romani, Barbara Banelli + Show 1 more

Open Access

https://doi.org/10.3389/fonc.2018.00448

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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.

Highlights

Glioblastoma (Glioblastoma Multiforme, GBM) is a rare tumor (Orphanet 360) that, being responsible for 4% of all tumor deaths and with a 5-years survival of 2%, is one of the deadliest human tumors [1] with the median survival ranging from 14 to 24–30 months depending from the molecular subtype of the tumor [2].GBM, like other tumors, harbors many genetic alterations that interfere with cancer-related pathways [3], clinical trials targeting molecular alterations in this tumor were largely unsuccessful so far [4,5,6]
In the last 30 years, the only significant improvement in OS occurred with the introduction of Temozolomide (TMZ) in addition to surgery and radiotherapy [7, 8]
GBM patients are stratified into two categories according to the methylation status of the O-6-methylguanine-DNA methyltransferase gene (MGMT) that repairs the DNA damages induced by TMZ and the patients whose tumor contains methylated MGMT have an overall survival of 21.7 months compared to the 12.7 months of those carrying unmethylated MGMT [9]

Summary

Introduction

Glioblastoma (Glioblastoma Multiforme, GBM) is a rare tumor (Orphanet 360) that, being responsible for 4% of all tumor deaths and with a 5-years survival of 2%, is one of the deadliest human tumors [1] with the median survival ranging from 14 to 24–30 months depending from the molecular subtype of the tumor [2].GBM, like other tumors, harbors many genetic alterations that interfere with cancer-related pathways [3], clinical trials targeting molecular alterations in this tumor were largely unsuccessful so far [4,5,6]. Only the molecules acting on DNA methylation and histone methylation/chromatin remodeling were tested in clinical trials. Both DNA methylation and histone modification, along with chaperon molecules, participate to chromatin remodeling conferring an exquisite plasticity to the genetic apparatus [13, 14].

Results

Conclusion