10054- CBMS-1 TARGETING POLY(ADP-RIBOSE) TO INDUCE SELECTIVE CELL DEATH IN IDH-MUTANT GLIOMAS

Abstract To develop a novel therapeutic approach targeting DNA repair mechanisms for isocitrate dehydrogenase (IDH) mutant gliomas, we examined the combined effects and mechanisms of poly(ADP-ribose) glycohydrolase (PARG) inhibitors (PARGi) and radiation therapy (IR). Poly(ADP-ribose) polymers (PAR chains) are essential DNA repair enzymes synthesized by poly(ADP-ribose) polymerase (PARP) using nicotinamide adenine dinucleotide (NAD) as a substrate. PAR chains are degraded by PARG, and their length is precisely controlled by the balance of PARP and PARG activities, playing crucial roles in DNA damage response and cellular stress reactions. Previous studies showed that the combination of PARGi and temozolomide (TMZ) exhibited selective cytotoxicity in IDH mutant glioma cells, and our study confirmed cell death due to a novel DNA repair vulnerability independent of NAD depletion. Experiments using patient-derived IDH mutant glioma cell lines demonstrated that the combination of PARGi and IR exhibited strong cytotoxicity towards IDH mutant cells. Additionally, lentivirus-mediated PARG knockout (KO) experiments showed high radiation sensitivity in PARG KO cells, and partial recovery of cytotoxicity with IDH inhibitors. These results suggest that the combination of PARGi and IR has synergistic effects specifically in IDH mutant cells. Furthermore, we analyzed the expression of DNA damage markers PAR and γH2AX over time using western blotting and immunofluorescence, and confirmed tumor reduction in a mouse model with IDH mutant PARG-KO cell lines treated with IR. PARGi, which have high selectivity and bioavailability, are expected to have lower systemic toxicity compared to conventional alkylating agents, and the synergistic cytotoxic effects could potentially reduce postoperative radiation doses. Particularly, since recurrent tumors after TMZ treatment often acquire mutations in DNA repair enzymes, this therapeutic strategy offers a promising new approach based on novel mechanisms.