Systematic Review of Epigenetic Therapies for Treatment of IDH-mutant Glioma

Abstract

Background: Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy.

Methods: We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively.

Results: A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%.

Conclusion: IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.

Keywords: Epigenetics; Glioblastoma; Glioma; HDAC; Histone deacetylase inhibitor; IDH.

Figure 1.

PRISMA diagram summarizing systematic review process.

Figure 2.

(A) Mechanism of IDH1m and IDH1m inhibitors. IDH1m produces 2-hydroxyglutarate (2-HG), which in turn inhibits histone demethylases. The loss of histone demethylases reverts DNA methylation patterns to those of progenitor cells, promoting tumorigenesis. IDH1m inhibitors aim to disrupt this process by directly inhibiting IDH1m. (B) Mechanism of histone deacetylase (HDAC) and HDAC inhibitors. HDAC decondenses chromatin, thereby allowing for gene expression. Mutant HDACs are products of gain-of-function mutations that upregulate multiple genes associated with increased cell survival, growth, and division, contributing to tumor formation. (C) Mechanism of bromodomains and their inhibitors. Bromodomains bind acetylated lysine residues and subsequently act as scaffold for transcription machinery. Bromodomain inhibitors may not have direct cytotoxic effects but inhibit double-strand break (DSB) repair, predisposing tumor cells to the cytotoxic effects of other chemotherapeutics. (D) Description of 5-azacitidine (5-AZ) mechanism of action. 5-AZ inhibits DNA methyltransferase (DNMT), leading to upregulation of immunomodulatory genes, namely cytokines and interferon. These gene products may leverage the host immune response to target tumor cells. IDH, isocitrate dehydrogenase.

Figure 3.

(A) Mechanism of PARP and PARP inhibitors. PARP normally repairs several mechanisms of DNA damage, including double-strand breaks (DSBs). In tumor cells that lack other forms of DNA repair (nonhomologous end-joining, homologous recombination, etc.), PARP is critical for their continued survival and proliferation. PARP inhibitors (PARPIs) take advantage of this fact, leading to cytotoxic accumulation of DSBs, ultimately leading to tumor cell death. (B) Characterized by a high metabolic rate, cancer cells often rely on. PARP, poly-ADP ribose polymerase.

Figure 4.

Comparison of percent progression-free patients at 6 months (PFS6) in patients receiving HDAC inhibitors relative to historical controls. Patients receiving HDAC inhibitors were less likely to be progression-free at 6 months post treatment though this was not significant (P = 0.07, OR = 0.53, 95% CI [0.27–1.05]). CI, confidence interval; HDAC, histone deacetylase; OR, odds ratio.