DDDR-13. A Brain-Penetrant Epigenetic Strategy to Overcome Therapy-Refractory Glioblastoma

Abstract Glioblastoma (GBM) remains uniformly fatal because the standard temozolomide (TMZ) + radiotherapy regimen is quickly thwarted by epigenetic adaptations that reactivate proliferation and blunt DNA-damage responses; mounting evidence implicates simultaneous up-regulation of lysine-specific demethylase 1 (KDM1A/LSD1) and histone deacetylase 2 (HDAC2) as a central driver of this resistance, yet no brain-penetrant agent has been available to co-target both enzymes. Here we show that MPT0G521, a dual KDM1A/HDAC inhibitor able to cross the blood–brain barrier, reverses this adaptive program. Integrated analyses of TMZ- and radiation-resistant GBM lines, public bulk datasets and 66 000 single cells revealed concerted over-expression of KDM1A and HDAC2, tight co-regulation with 50 core cell-cycle genes, and enrichment of LSD1-high NPC/OPC-like populations at invasive margins; high expression of either gene predicted significantly worse overall survival in CGGA cohorts (log-rank p < 0.01). In both parental and TMZ-resistant A172 and patient-derived Pt#3 cells, MPT0G521 produced dose- and time-dependent growth inhibition, suppressed clonogenicity, induced G2/M arrest, and triggered caspase-3/PARP-mediated apoptosis. Mechanistically, treatment raised H3K4me1/2 and H3K9/K14ac without altering core histone levels, confirming effective blockade of KDM1A demethylase and HDAC deacetylase activities. These findings identify KDM1A/HDAC2 over-expression as a tractable epigenetic vulnerability in therapy-refractory GBM and position MPT0G521 as a promising lead compound for overcoming TMZ resistance and improving clinical outcomes.