Dipg-31. hif-1a and hif-2a combinatorial targeting or how to reverse their balanced oncogenic impact

Abstract HIF-1a and HIF-2a are master regulators operating during tumor hypoxia. Few data are available on their role in pediatric high-grade gliomas (pHGGs), in which recent insights on metabolism and immunotolerance induction through hypoxia-driven mechanisms might opening the path to study further this process and their molecular actors. Our study investigated and confirmed the balanced dependency of both transcription factors in pHGGs at protein levels, but not in their transcriptional reprogramming. We also examined how HIF-1a and HIF-2a are operating during acute and chronic hypoxia in a spatiotemporal cell setting. HIF-1a was clearly correlated within pHGGs samples and models to acute and moderate hypoxia, whereas HIF-2a was associated to H3.3K27M mutant DIPG and chronic hypoxia. The impact of targeting both transcription factors in pHGG-derived models was on cell proliferative and invasive mechanisms, especially when studying this drug testing in engineered neural tissues. We might position those new targets as an innovative way to counterpart their hyperactivation in tumor core hypoxia and to propose them as an innovative approach interfering with cell-to-cell adhesion and synaptic interactions with normal brain cells.