DIPG-37. AUGMENTING RADIATION SENSITIVITY IN DMG/DIPG BY TARGETING TP53 DEPENDENCY AND INHIBITING DNA PROTEIN KINASE PATHWAY

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Abstract BACKGROUND Diffuse midlines gliomas (DMGs) are lethal pediatric brain tumors, with an overall survival rate of less than 12 months. Radiotherapy treatment (RT) only provides a transient clinical response, with an average survival increase of about 3 months. At the cell level it induces DNA damages, leading to tumor cell death. Although, DMGs are tumors known to be resistant to any therapy, as the tumor recurs most often within a few months post radiation. Peposertib, a DNA Protein Kinase (DNA-PK) inhibitor, is a potent radiosentitizer that crosses the blood brain barrier and has shown RT-combination efficacy in other cancers by enhancing DNA double-strand breaks (DSB) inducing agents including ionising radiation. Methods and RESULTS DNA-PK plays a key role in one of the main pathways involved in the repair of DNA double-strand breaks (DSB), allowing tumor cells to repair their DNA and continue proliferation. To further investigate Peposertib and its potential for clinical intervention, we explored Peposertib’s radiosensitizing activity on DMG preclinical in vitro models. In vitro viability assays with RT alone and in combination with Peposertib, were carried out using DMG cell lines carrying either the wild-type or mutated version of TP53. To further validate our results, immunofluorescence assays post-combination treatment were performed to assess DDR pathway disruption by studying the number of foci per nucleus of DNA damage markers yH2AX and P53BP1. RESULTS Remarkably, combinational treatment of Peposertib with RT resulted in a significant decrease in human primary DMG cells viability. Interestingly, Peposertib was effective in increasing RT sensitivity in TP53WT DMGs. However, the same good response was not observed in the DMG cell lines carrying TP53MUT, indicating a possible correlation between TP53 mutational status and response to therapy. Additionally, we demonstrated that Peposertib induces cell death. This was observed and determined through quantification analysis of DNA damage markers yH2AX and P53BP1 therefore to DDR pathway disruption. CONCLUSIONS Our current findings underscore Peposertib’s potential as a targeted therapeutic agent against DMGs, offering a better understanding of what drives resistance to radiotherapy. By targeting DDR pathway key factors we will increase sensitivity to radiation in vitro and in vivo in DMGs.

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