Chemoradiosensitization of Malignant Glioma through Co-inhibition of Redundant DNA Repair Pathways
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Date
2015-08-07
Authors
Packer, Matthew
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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.
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Keywords
malignant glioma (MG), Redundant DNA