Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Area of Science:

• Pediatric Oncology
• Cancer Therapeutics
• Epigenetics

Background:

• Diffuse intrinsic pontine glioma (DIPG) is an aggressive, incurable childhood brain tumor necessitating novel therapeutic approaches.
• Existing treatments are limited, highlighting the urgent need for innovative strategies targeting DIPG's underlying molecular mechanisms.

Purpose of the Study:

• To evaluate the anti-cancer efficacy of CBL0137, a novel compound targeting the facilitates chromatin transcription (FACT) complex, in diffuse intrinsic pontine glioma (DIPG).
• To investigate the molecular mechanisms of CBL0137 action, including its effects on tumor suppressor pathways and histone modifications.
• To assess the therapeutic potential of combining CBL0137 with panobinostat, a histone deacetylase inhibitor, for DIPG treatment.

Main Methods:

• Cytotoxicity assays were performed on patient-derived DIPG cell cultures treated with CBL0137.
• In vivo efficacy was assessed using an orthotopic DIPG mouse model treated with CBL0137.
• Molecular analyses included Western blotting to examine protein activity (TP53, Rb), histone modifications (acetylation, trimethylation), and pathway inhibition (Rb/E2F1).

Main Results:

• CBL0137 demonstrated potent cytotoxic activity against DIPG cultures by restoring tumor suppressor TP53 and Rb activity.
• Treatment with CBL0137 significantly extended survival in mice with orthotopic DIPG.
• CBL0137 treatment restored histone H3 acetylation and trimethylation, with SPT16 interacting with H3.3K27M.
• Combined CBL0137 and panobinostat treatment inhibited the Rb/E2F1 pathway, induced apoptosis, and significantly prolonged survival in DIPG-bearing mice.

Conclusions:

• CBL0137 exhibits significant preclinical efficacy against diffuse intrinsic pontine glioma (DIPG) by targeting chromatin remodeling and restoring tumor suppressor function.
• The combination of CBL0137 and panobinostat presents a promising therapeutic strategy for DIPG, warranting further clinical investigation.