Peer-reviewed article
HGG-09. TARGETING FACILITATES CHROMATIN TRANSCRIPTION (FACT) AS A NOVEL STRATEGY THAT ENHANCES RESPONSE TO HISTONE DEACETYLASE (HDAC) INHIBITION IN DIPG
Ehteda A, Simon S, Franshaw L, Giorgi F, Liu J et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a basic science and preclinical research paper on a novel drug combination for treating DIPG (diffuse intrinsic pontine glioma), a rare childhood brain tumour. The study reports laboratory and animal model experiments showing that CBL0137, a chromatin-targeting compound, works synergistically with HDAC inhibitors to kill DIPG cancer cells and extend survival in mouse models. The research is focused on understanding drug mechanisms and identifying promising candidates for clinical testing rather than evaluating child health or well-being outcomes.
Key points
- CBL0137 induced apoptosis in DIPG neurospheres and significantly improved survival in orthotopic mouse models
- Combination of CBL0137 with panobinostat showed synergistic activity, profoundly enhancing cell death in vitro and significantly prolonging survival in two independent orthotopic models
- CBL0137 targets the FACT complex and directly addresses the H3.3K27M epigenetic defect in DIPG cells
- A paediatric clinical trial of CBL0137 will be opened through the Children's Oncology Group with expansion for DIPG patients
Limitations
This is preclinical research based on cell cultures and animal models; it does not evaluate actual outcomes in children with DIPG or provide evidence on treatment effectiveness, tolerability, or quality of life in human patients. The study is designed to justify clinical trial development rather than assess real-world child health impacts.
Abstract
Abstract DIPG is an aggressive and incurable childhood brain tumour for which new treatments are needed. A high throughput drug screen of 3500 pharmaceutical compounds identified anti-malarials, including quinacrine as having potent activity against DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is a novel anti-cancer compound which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier and has recently completed Phase I testing in adult patients. CBL0137 induced apoptosis in DIPG neurospheres and had profound cytotoxic activity against a panel of DIPG cultures. In a DIPG orthotopic model, treatment with CBL0137 significantly improved survival. We found that treatment with CBL0137 up-regulated TP53 and increased histone H3.3 acetylation and tri-methylation in DIPG cells. We therefore examined the interaction between CBL0137 and the histone deacetylase (HDAC) inhibitor panobinostat. In vitro experiments showed that the two agents had profound synergistic activity against DIPG neurospheres in clonogenic assays and enhanced caspase activation and apoptosis. The FACT subunit SSRP1 was found to directly interact with H3.3K27M and treatment with CBL0137 targeted this epigenetic defect, restoring histone H3.3 trimethylation and leading to tumor cell death. Transcriptomic analysis and immunoblotting indicated that combination treatment activated signalling pathways controlled by Retinoblastoma (RB)/E2F1 and subsequently increased phosphorylation and enzymatic activity of enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged survival in two independent orthotopic models of DIPG, while histological analysis showed restoration of H3K27me3 and decreased Ki67 positive cells. In addition to panobinostat, CBL0137 has been found to combine synergistically in vitro and in vivo with PARP and BET inhibitors. Given these promising results, a paediatric trial of CBL0137 will open through the Children’s Oncology Group with an expansion cohort for DIPG patients.