ReviewGlioma epigenetics: From subclassification to novel treatment options
Introduction
Gliomas are among the most common primary brain tumors in adults and account for over 70% of malignant brain tumors, of which glioblastoma is the most common and most malignant (World Health Organization [WHO] grade IV) with an incidence rate of 3.2 per 100 000 population [1]. The median survival is less than 2 years with the current standard of care of maximal safe resection, followed by combined radio-chemotherapy with the alkylating agent Temozolomide [2] that may be modestly improved with the addition of Tumor Treating Fields [3]. Glioblastomas are notorious for resistance to therapy, and despite numerous efforts, the addition of targeted agents against genetic or biological hallmarks of gliomas have largely failed [4]. Lower grade gliomas (LGG) WHO grade II and III are less common and affect younger patients. They have a better prognosis and show some sensitivity to therapy that both depend on the molecular subtype [5], [6]. After resection LGG patients may first just be followed according to a “wait and see” strategy that depends on clinical and molecular risk factors, before entering treatment with different schemes of radio- or chemotherapy, or a combination thereof [6], [7], [8]. The optimal therapy is debated, however treatment related effects on cognitive function require risk-adapted (molecularly driven) treatment strategies, given that LGG patients may live more than 15 years [9].
Section snippets
Epigenetic subtypes of gliomas
Insights into the molecular landscape of diffuse gliomas have revealed characteristic genetic and epigenetic profiles which have clarified their etiologic evolution [5], [10], [11], [12], [13], [14], [15], [16] and allowed their classification into distinct molecular subtypes that have been integrated into the 2016 WHO classification (Fig. 1) [17]. Mutations in the epigenetic modulator genes isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2), and in the histone genes H3F3A or HIST1H3 B have become
Targeting the glioma epigenome
Several different approaches of targeting epigenetic alterations have been or are being tested in clinical trials: those targeting mutant IDH either by small molecule inhibitors, or as target for vaccination in the respective patient population; and those targeting epigenetic modifiers affecting large parts of the epigenome such as BETi, HDACi, DNMTi, and EZH2i (Fig. 3). Respective clinical trials, as available on clinicaltrials.gov, are summarized in Table 1.
Conclusions
Discoveries of the last decade have completely changed our view on the genomic and epigenetic landscape of human gliomas. Driver mutations in epigenetic regulator genes have clarified their etiology and defined molecular subtypes with distinct biology. Consequently, epigenetic biomarkers play now a central role in tumor classification and decision making for stratified therapies. A whole arsenal of epigenetic drugs promises to target epigenetically deregulated pathways by interfering on several
Funding sources
Olga Gusyatiner is funded by the Swiss National Science Foundation (31003A_163297 to M. Hegi).
Conflict of interest statement
Olga Gusyatiner and Monika Hegi receive institutional research funding for institutional research project from Orion Corporation. M. Hegi received research funding for institutional research project from Novocure. She served as a consultant to Bristol-Myers Squibb. The Institution receives free testing from MDxHealth.
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