Abstract Pediatric diffuse midline glioma, H3K27-altered is a lethal form of brain tumor with a median survival of less than 12 months. The oncohistone mutation, H3K27M that is observed in ∼80% of the patients potentiates universal H3K27 hypomethylation and a subsequent hyperacetylation at this residue. These tumors are resistant to chemotherapy and radiotherapy is mostly a palliative effort. Therefore, there is a critical need for novel effective therapies. We and our collaborators have successfully demonstrated the therapeutic efficacy of the oncolytic adenovirus (OV), Delta-24-RGD, in adult glioblastoma as well as in pediatric DIPG in phase I clinical trials (NCT00805376 and NCT03178032, respectively). Based on the well-established process of the early viral protein, E1A, binding to the acetyltransferase enzymes, P300/CBP during virus infection and the previously demonstrated observation that P300-mediated tumor acetylation maintains the immunosuppressive environment in several cancer types, we hypothesized that pharmacological inhibition of P300 will enhance the antitumor immunity mediated by Delta-24-RGD in DMG/DIPG. Using immunoblot studies, we showed that Delta-24-RGD induced a time-dependent loss of H3K27ac and H3K18ac in a panel of clinically significant human and murine DMG cells. Furthermore, we observed that combining Delta-24-RGD with the small-molecule P300/CBP inhibitor, C646, in vitro reduces cell viability in DMG cells with ZIP scores ranging upto 16.82, indicating high synergy. We also observed a decrease in the transcripts of immunosuppressive and T-cell exhaustion inducing factors with the combination treatment, signifying the role of P300 inhibition in suppressing regulatory immune effects that are upregulated following OV. Importantly, In vivo, we observed reduced tumor burden in mice treated with a combination of Delta-24-RGD and C646 compared to the monotreatment or the control. In conclusion, our results demonstrate the enhanced anti-tumor effect of P300/CBP inhibitors combined with Delta-24-RGD in treating DMG/DIPG, thereby, providing strong rationale to test this combination in a clinical setting.
Parthasarathy et al. (Fri,) studied this question.