EXTH-63. COMBINED INHIBITION OF TOP1 AND PARP: A NOVEL THERAPEUTIC STRATEGY FOR GBM WITH PTEN DEFICIENCY

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and lethal type of brain tumor. Activation PI3K/mTOR pathway along with loss its primary negative regulator, phosphatase tensin homolog (PTEN), occurs in nearly 50% GBM patients. As PTEN known to promote DNA damage repair deficiency, here we investigated whether deficiency presents a vulnerability simultaneous induction suppression mechanisms by combining topoisomerase I (TOP1) PARP inhibitors. METHODS We used patient-derived cells stem-like determine response LMP400 (Indotecan), novel non-camptothecin TOP1 inhibitor, inhibitors Olaparib or Niraparib. Treatment efficacy was also determined using cell viability, cycle, damage, repair, apoptosis assays pair isogenic PTEN-null PTEN-WT glioma lines derived from genetically engineered mouse model. RNAseq analysis performed identify treatment-induced dysregulated pathways. RESULTS PTEN-deficient are highly sensitive rescue lessens sensitivity treatment. Combining inhibitors, Niraparib, leads synergistic cytotoxicity. LMP400/Niraparib combination induces G2/M cycle arrest, homologous recombination (HR)-related proteins activation caspase 3/7 activity significantly more compared cells. Gene set enrichment revealed as well death Finally, CRISPR-Cas9 KO screening suggests that not likely be substrate for ABC transporters, suggesting penetration supporting use tumor CONCLUSION Combined inhibition antiglioma effects selectively glioblastoma cells, providing strong scientific premise clinical trial combined treatment Niraparib subset deficiency.