Emerging applications of hypomethylating agents in the treatment of glioblastoma (Review)

Abstract

DNA hypomethylating agents (HMAs) such as decitabine and 5-azacytidine have established roles in the treatment paradigms for myelodysplastic syndrome and acute myelogenous leukemia, where they are considered to exert their anticancer effects by restoring the expression of tumor suppressor genes. Due to their relatively favorable adverse effect profile and known ability to pass through the blood-brain barrier, applications in the treatment of glioblastoma (GBM) and other central nervous system malignancies are under active investigation. The present review examines the types of HMAs currently available, their known and less-understood antineoplastic mechanisms, and the evidence to date of their preclinical and clinical efficacy in glioblastoma and other solid malignancies. The present review discusses the potential synergies HMAs may have with established and emerging GBM treatments, including temozolomide, immune checkpoint inhibitors and cancer vaccines. Recent successes and setbacks in clinical trials for newly diagnosed and recurrent GBM are summarized in order to highlight opportunities for HMAs to improve therapeutic responses. Challenges for future clinical trials are also assessed.

Keywords: decitabine; glioblastoma; hypomethylating agent; immunotherapy; temozolomide.

Figure 1

Proposed mechanism of action of DAC and TMZ. Once DAC enters the cell, it undergoes triphosphorylation, converting it to 5-aza-dCTP, which is incorporated into DNA during S-phase in place of cytosine. 5-aza-dCTP traps and inactivates DNMTs, causing exome-wide changes in gene expression mediated by promoter demethylation, gene body demethylation and changes in TF expression. MLH1 is upregulated, increasing levels of O6-methylguanine produced by TMZ and futile MMR activity. This ultimately results in enhanced cytotoxicity due to DNA double-strand break formation, cell cycle arrest and apoptosis. The effects of TMZ are exerted through its spontaneous decarboxylation to MTIC, which is unstable and degrades into the reactive CH3N2+. 5-aza-dC, 5-aza-2'-deoxycytidine; 5-aza-dCTP, 5-aza-2'-deoxycytidine-5'-triphosphate; CH3N2+, methyldiazonium ion; DAC, decitabine; DNMT, DNA methyltransferase; Me, methyl group; MGMT, methylguanine methyltransferase; MLH1, mutL homolog 1; MMR, mismatch repair; MTIC, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide; TF, transcription factor; TMZ, temozolomide.