Enhancing chemotherapeutic responses in CNS malignancy through suppression of hyperactive DNA damage repair pathways

Abstract

Current methods to treat medulloblastoma (MB) and malignant glioma (MG) are highly intrusive with three-year survival. Recurrence is high due to chemoradio-resistance. We are targeting DNA repair pathways through inhibitors of DNA repair proteins; Poly (ADP-Ribose) Polymerase (PARP1i), DNA-dependent protein kinase (DNA-PKi) and Ataxia-Telangiectasia Mutated (ATMi) to sensitize tumours to DNA damaging agents. However, differing tumours have variable expression of these enzymes/repair pathway(s) activity, therefore; their identification and inhibition may enhance current treatment efficacy. High-throughput comet assay revealed enhanced drug-mediated tumour cell death in MB cell lines with TOPI+PARP1i with activation of specific repair pathways. Further, RNA-Seq analysis revealed PARP1 upregulated in DAOYMB and downregulated in D283; while BRCA1 downregulated in DAOYMB and upregulated in D283MB, suggesting defective Homologous recombination (HRR) pathway, hence synthetic lethality in MB cell line (DAOYMB). Therefore, I have identified unique DNA repair enzymes, which may mediate specific differential chemo-radioresistant phenotypes in MB.