TMIC-53. Novel therapy for diffuse midline glioma: Targeting oncohistone drivers with P300/CBP inhibition and Delta-24-RGD

There is no effective treatment for H3K27-altered diffuse midline glioma (DMG). The hallmark mutation, H3K27M, observed in approximately 80% of the patients, influences universal H3K27 hypomethylation and subsequent hyperacetylation at this residue and is associated with tumor aggressiveness. We and our collaborators have demonstrated the therapeutic efficacy of the oncolytic adenovirus Delta-24-RGD in phase I clinical trials (NCT00805376 and NCT03178032) for the treatment of both adult and pediatric patients with gliomas. Based on previous studies outlining the process of early adenoviral protein E1A binding to the acetyltransferase enzymes P300/CBP during virus infection and the documented cases of P300-mediated tumor immunosuppression in several cancer types, we hypothesized that pharmacological inhibition of P300 would enhance the antitumor immunity mounted by Delta-24-RGD in DMG and improve survival. Histone post-translational modification analyzed by mass spectrometry demonstrated the widespread hypoacetylation effect of Delta-24-RGD. Validating these findings with western blot studies, we demonstrated that Delta-24-RGD induced loss of H3K27ac and H3K18ac in a panel of clinically significant human and murine DMG cells. Furthermore, we observed synergistic anti-glioma effects of Delta-24-RGD and P300/CBP acetyltransferase inhibitors, C646 and CPI-1612, in vitro (ZIP scores ranging up to 15.90). Proteome array experiments revealed an increase in expression of inflammatory cytokines involved in T-cell recruitment and activation, 14 days post-virus treatment in the combination-treated mice, indicating that P300 inhibition maintains an inflammatory milieu after Delta-24-RGD. Importantly, the combination of Delta-24-RGD and P300 inhibition reduced tumor burden in clinically relevant models of pediatric DMG. In conclusion, our results demonstrate that the dual target of the oncohistone driver of DMG induces a potent anti-cancer effect, providing a strong rationale for the translation of this combination to the clinical scenario.