Dept. of Pharmacology and Therapeutics, Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Ave, Winnipeg, Manitoba, R3E 0V9, Canada
Current brain cancer treatment strategies are inadequate as there are few effective treatments and currently employed tumour-killing regiments often lead to a variety of side effects and general systemic toxicity. These grim facts emphasize the absolute requirement to dramatically improve upon current anti-cancer therapeutic strategies. My proposed research seeks to ameliorate current brain cancer treatment paradigms. I have found that two proteins responsible for the DNA damage repair response, ATM and TDP1, coordinate the modification and resolution of Topoisomerase-1 at DNA breaksites (Top1-DNA). We hypothesize that ATM and TDP1 coordinate neurodevelopment by resolving Top1cc in vivo and co-inhibition of ATM and TDP1 will sensitize brain tumour cells to chemoradiotherapy by augmenting Top1cc levels thereby enhancing tumour cell killing. We will determine whether ATM and TDP1 facilitate DNA single-strand break repair to resolve Top1-DNA covalent complexes (Top1cc). We will then inhibit ATM and TDP1 to chemoradiosensitize brain tumours and we will develop novel TDP1 inhibitors to treat brain tumors both in vitro and in vivo. These findings are important considering the functional strategy of utilizing frontline DNA damaging chemotherapy and the need to develop innovative new treatment strategies for deadly brain cancers.