Modulating DNA Repair Pathways In The Treatment Of Malignant Brain Tumours

Sachin KATYAL, University of Manitoba and CancerCare Manitoba , Canada
PACKER M. 1,2 , SALEH A. 2

1 Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
2 Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada

Purpose: Current methods to treat glioblastoma multiforme (GBM) are highly invasive, lead to poor quality-of-life and an abysmal patient survival rate thus making GBMs one of the most difficult-to-treat and deadliest form of all primary CNS malignancies. The targeted use of Topoisomerase-1 (Top1) poisons/inhibitors to sensitize or augment tumour cell killing is a long-standing and powerful tool in cancer therapy. A number of trials utilizing Top1 inhibitors to manage GBM have shown promise.
We have uncovered a novel functional requirement for ATM (Mutated in Ataxia Telangiectasia) in resolving oxidative DNA breaks and Topoisomerase 1-DNA covalent complexes (Top1cc), a DNA-protein intermediate that can generate DNA breaks upon collision with the transcriptional machinery or DNA replication forks. These data have identified Top1cc as the first specific endogenous pathogenic neural DNA lesion associated with loss of ATM and heritable pediatric neurodegenerative disease. Furthermore, biochemical and genetic studies identified collaboration of ATM and TDP1 (Tyrosyl-DNA Phosphodiesterase 1) in the resolution of Top1cc during neurodevelopment.
Methods: We hypothesize that co-inhibition of ATM and TDP1 will sensitize brain tumours to Top1-dependent chemotherapy by augmenting Top1cc levels and anti-tumour success. Genetic and biochemical methods to co-inhibit ATM and TDP1 and improve the efficacy of Top1 poisons include cell-based DNA damage repair and viability assays and in vivo brain tumour regression assays using mouse xenograft models.
Results: We have found that brain tumour cell killing via Top1-dependent inhibition is greatly enhanced through an ATM and TDP1 co-inhibition strategy. We are presently validating these results in vivo.
Conclusions: ATM and TDP1 co-inhibition represents an effective two-pronged approach to chemoradiosensitize CNS tumours. As TDP1 antagonizes Top1cc formation and efficacy of Top1 poisons such as the camptothecin (CPT) cohort of drugs, my findings will improve existing Top1-mediated anti-cancer strategies by enhancing tumour cell killing while reducing clinical doses and patient side-effects.