Chemoradiosensitization of Malignant Glioma through Co-inhibition of Redundant DNA Repair Pathways

Abstract

The objective of common front-line radiation and chemotherapeutic strategies used in the treatment of brain tumours is to induce DNA breaks and overwhelm the cellular DNA repair machinery thus promoting genomic damage and tumour cell death. However, as the intrinsic cellular DNA repair process counteracts the therapeutic efficacy of this strategy, high radiation and drug doses are required which result in harmful neural and systemic side effects. We seek to ameliorate current brain cancer killing paradigms by identifying ways to dysregulate cellular DNA repair pathways in tumours and improve therapeutic success. In this regard, DNA damage repair pathways are an ideal clinical target as we can specifically kill cancer cells by lowering the radio- and chemotherapeutic threshold of tumour cell genotoxicity by inhibiting redundant DNA repair pathways. We have uncovered an unexpected role for ATM in the resolution of Top1cc, a particularly genotoxic lesion often exploited in the clinical management of cancer through the use of the camptothecin (CPT) family of anticancer drugs. Our neurodevelopmental findings also demonstrate a coordinated genetic and biochemical relationship between ATM and TDP1 in the resolution of the Top1cc lesion. Through co-inhibition of ATM and TDP1, we will sensitize brain tumour cells to chemoradiotherapy by augmenting Top1cc levels thereby enhancing tumour cell killing. We believe that this strategy will lead to an improved Top1-mediated cancer treatment paradigm that will augment antitumour therapeutic efficacy, patient survival and quality-of-life.