DIPG-24. BRD4 INHIBITION AS A RADIOSENSITIZER THROUGH BLOCKING DNA REPAIR FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA

Abstract Diffuse intrinsic pontine glioma (DIPG) is one of the devastating childhood cancers. Radiation therapy (RT) remains only effective treatment yet provides a 5-year survival rate 1%. Several clinical trials have attempted to enhance RT efficacy by combining it with radiosensitizing agents, though none been successful in doing so. Given this, there critical need identify therapeutics anti-tumor activity DIPG. Here, we identified BRD4 inhibitors as candidate radiosensitizers from high throughput drug screening. DIPG cells show increased H3 K27 acetylation (H3K27ac) levels, which bind BET bromodomain protein 4 (BRD4) and are strongly associated active transcription. We tested two (BRD4i: AZD5153 JQ-1) well genetic depletion, observed enhancement radiation-induced DNA damage, confirming BRD4i potential evaluated effects on gene expression using RNAseq, significant inhibition DNA-repair proteins such BRCA1 RAD51. CUT-RUN qPCR showed decreased H3K27ac at RAD51 promoters. Combination inhibited cell viability significantly clonogenic assay, apoptosis also cycle arrest. Radiation-induced double-strand break (DSB) repair was prolonged levels gH2AX 53BP1 likely due DNA-repair. In vivo studies revealed animals treated combination comparison either monotherapy. Together, these results highlight radiosensitizer provide rationale for developing radiation