EXTH-11. TELOMERASE INHIBITION IS AN EFFECTIVE THERAPEUTIC STRATEGY IN TERT PROMOTER-MUTANT GLIOBLASTOMAS MODELS WITH LOW TUMOR BURDEN

Abstract Glioblastoma targeted therapeutics have been challenging to develop due significant inter- and intra-tumoral heterogeneity. While many activated oncogenes in glioblastoma are subclonal, TERT promoter mutations commonly occur as clonal events found up 80% of IDH-wildtype glioblastomas. Given the high prevalence nature glioblastoma, telomerase is considered a promising therapeutic target for this deadly cancer. Prior studies validated hypothesis, demonstrating that knockout transcription factor GABPA, which selectively binds mutant promoter, well base editing-mediated correction mutations, toxic TERTpromoter However, an important limitation strategy cancer cell death does not immediately after ablation, but rather several divisions required reach critically short telomeres. We therefore hypothesize inhibition would only be effective low tumor burden In study, we used CRISPR interference knock down expression promoter-mutant lines patient derived models. then measured viability assessed features telomere crisis by measuring length chromatin bridge formation. Lastly, doxycycline inducible system vivo early late formation process. demonstrated cells sensitive undergo crisis. vivo, inhibited when knockdown induced shortly implantation, high. This work supports idea suitable patients with burden, example adjuvant setting surgical debulking chemoradiation.