Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in 
children with 5-year survival rates of only 2%. About 85% of all DIPG are 
characterized by a lysine-to-methionine substitution in histone 3, which leads 
to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. 
Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal 
(BET) protein BRD4, and leads to the reprogramming of the enhancer landscape 
contributing to the activation of DIPG super enhancer-driven oncogenes. The 
activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 
and associated with acetylation of nucleosomes at super enhancers (SE). In 
addition, CBP contributes to transcriptional activation through its function as 
a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET 
inhibitor (JQ1) led to the reduction of tumor-related characteristics. 
Interestingly, combined treatment induced strong cytotoxic effects in 
H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin 
immunoprecipitation revealed that these effects were caused by the inactivation 
of DIPG SE-controlled tumor-related genes. However, single treatment with 
ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental 
super enhancers. Combinatorial treatment reversed the inadvertent activation of 
these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment 
on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type 
pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors 
is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent 
activation of detrimental SE programs in comparison with monotherapy.