A novel dual epigenetic approach targeting BET proteins and HDACs in Group 3 (MYC-driven) Medulloblastoma

Abstract

Background Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies. Epigenetic deregulation is very common in MYC-driven MB. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs. This study aimed to investigate the therapeutic potential of inhibiting the BET proteins and HDACs together in MB. Methods Using clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat), we evaluated the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts and examined underlying molecular mechanism(s). Results Co-treatment of JQ1 or OTX015 with panobinostat synergistically suppressed growth/survival of MYC-amplified MB cells by inducing G2 cell cycle arrest and apoptosis. Mechanistic investigation using RNA-seq revealed that co-treatment of JQ1 with panobinostat synergistically modulated global gene expression including MYC/HDAC targets. SYK and MSI1 oncogenes were among the top 50 genes synergistically downregulated by JQ1 and panobinostat. RT-PCR and western blot analyses confirmed that JQ1 and panobinostat synergistically inhibited the mRNA and protein expression of MSI1/SYK along with MYC expression. Reduced SYK/MSI expression after BET (specifically, BRD4) gene-knockdown further confirmed the epigenetic regulation of SYK and MSI1 genes. In addition, the combination of OTX015 and panobinostat significantly inhibited tumor growth in MYC-amplified MB xenografted mice by downregulating expression of MYC, compared to single-agent therapy. Conclusions Together, our findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB.

Combination drug screen targeting glioblastoma core vulnerabilities reveals pharmacological synergisms

“…Recent studies have provided mechanistic and pre-clinical evidence for the combination of HDAC inhibitors (HDACi) with BETi, even leading to the development of dual inhibitors. 54 , 55 , 56 , 57 Herein, our combination drug screen revealed that HDACi Panobinostat mostly antagonizes with all tested BETi in the murine GL261 cell line. While these unexpected results were confirmed in the GL261 spheroid model using Panobinostat and Birabresib, a synergistic effect was observed with the same drug combination in the U87 spheroid model.…”

Pathogenic role of super-enhancers as potential therapeutic targets in lung cancer

“…A combination of inhibitors targeting epigenetic regulators histone deacetylase (HDAC) and BET exerted synergistic antitumoral effects in pancreatic cancer (He et al, 2020), glioblastoma (Gusyatiner et al, 2021), and medulloblastoma (Kling et al, 2022). In SCLC xenograft mice, JQ1 and the histone deacetylase 6 (HDAC6) inhibitor ACY-1215 combined to exert antitumor activity dependent on the presence of NK cells (Liu et al, 2018).…”

The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies

“…It important to note that the use of combination therapies has also emerged as an appealing route in the fight against group 3 medulloblastoma due to the aggressiveness and resistance of this subgroup. For instance, it has been shown that the combination of JQ1 with a CDK2 inhibitor (Milciclib), an mTOR inhibitor (BEZ235), or a pan-HDAC inhibitor (Panobinostat) resulted in synergistic anti-cancer effects in MYC-driven group 3 medulloblastoma and amplified the potential of each of the combined agents [131][132][133]. The activity of the pathway is dependent on the Gamma secretase cleavage of the NOTCH receptor, which results in the dissociation of NICD.…”