DDDR-17. PTRF/Cavin1, from a biomarker to a therapeutic target in glioblastoma

Abstract BACKGROUND Polymerase I and transcript release factor (PTRF/Cavin1) has emerged as a promising therapeutic target in glioblastoma (GBM), functioning as a biomarker in glioma and serum exosomes. Its interaction with caveolin-1 facilitates small extracellular vesicles (sEVs) secretion, which promotes temozolomide (TMZ) efflux and chemoresistance. Targeting PTRF thus represents a novel strategy to overcome treatment resistance in GBM. METHODS Computer-aided drug design (CADD) identified EPIC-1042, a PTRF inhibitor, and EPIC-0726, a PTRF-targeting proteolysis-targeting chimera (PROTAC) degrader. EPIC-1042’s inhibition of PTRF–caveolin-1 binding was validated via biotin-streptavidin pull-down and co-immunoprecipitation (Co-IP). Western blotting, nanoparticle tracking analysis (Nanosight), Co-IP assays and immunofluorescence elucidated the mechanisms of EPIC-1042 and EPIC-0726. In vivo studies assessed tumor growth suppression and TMZ sensitization. RESULTS EPIC-1042 bound PTRF, disrupting its interaction with caveolin-1, reducing sEVs secretion and TMZ efflux. It also promoted autophagic degradation of PARP1 by enhancing the binding of p62 to PARP1 and promoting its translocation into autolysosomes. EPIC-0726 induced ternary complex-dependent PTRF degradation via the ubiquitin-proteasome system (UPS), reducing RBX1 stability. This suppressed K63-linked ubiquitination-driven ERK1/2/AKT activation while stabilized p21 via impaired K48-mediated degradation. In vivo, both compounds enhanced TMZ efficacy, with EPIC-0726 demonstrating superior potency over EPIC-1042. CONCLUSIONS Two novel PTRF-targeting therapeutic agents were developed: EPIC-1042 disrupts the PTRF–caveolin-1 interaction, while EPIC-0726 selectively induces PTRF degradation via the UPS. Both agents enhance the efficacy of TMZ in vitro and in vivo. Significantly, EPIC-0726 demonstrates superior potency through activating proteolysis strategy-enhanced TMZ efficacy by ERK1/2/AKT kinase suppression and p21 stabilization (PEAKS) via the PTRF-RBX1 regulatory axis. These findings warrant clinical translation of EPIC-1042 and EPIC-0726 as backbone therapeutics for combinatorial regimens in GBM treatment.