DDDR-17. CHEMOTHERAPEUTIC STRESS INDUCES NONCANONICAL HIF1Α SIGNALING UNDER NORMOXIA IN GLIOBLASTOMA DRIVING THERAPEUTIC RESISTANCE

Abstract Glioblastoma (GBM) is an aggressive brain tumor with no cure. Standard treatment includes adjuvant, concomitant temozolomide (TMZ) and radiation, but most patients do not survive more than 15 months. Tumor adaptations to contribute glioblastoma chemoresistance recurrence, hypoxia inducible factor subunit alpha (HIF1α) downstream effectors are implicated in attenuated therapeutic responses. We have previously shown that TMZ-dependent hijacking of HIF1α signaling under normoxia independent from physiological the core. Our results further showed TMZ promotes accumulation enhancing stem-like characteristics GBM cells driving therapy-resistant populations involved recurrence. However, noncanonical mechanisms well understood preventing success inhibitors thus far. Here, we investigate how induces oxygen-independent manner by characterizing HIF1a binding profile post-therapy. cultured patient-derived xenograft (PDX) models vitro found expression response element (HRE) activity peak 96h post-therapy using western blot luciferase assays. lab also performed a whole-genome CRISPR-Cas9 knockout screen over 28 days determine genetic drivers aggression. was be particularly enriched this screen, supporting role chronic for proliferation (p-value < 0.05). show therapy prevents proteasome-dependent degradation through reduced PHD2 VHL allowing nuclear translocation immunocytochemistry. Thus, immunoprecipitation proteomic characterization establish uniquely regulates stabilization absence oxygen tension, these will presented. subsequently characterize regulatory post-translational modifications HIF1α. Elucidating molecular therapy-mediated regulation can produce better targets increase efficacy.