Abstract 2194: Tyrosyl DNA phosphodiesterase I is a prognostic factor and its inhibition synergizes response to topoisomerase poisons in malignant glioma.

Malignant Glioma is the most common type of primary brain tumors in adults accounting for about 80% of all gliomas. Despite the advances in treatment and diagnosis, the prognosis of malignant glioma is still poor with a median survival less than a year for glioblastoma patients. Targeting DNA-repair mechanisms is a clinically relevant option for enhancing response to DNA-damaging anticancer agents. TDP1 has been recently discovered to be responsible for the repair of the irreversible DNA-topoisomerase I covalent complexes produced by topoisomerase I poisons. Other studies have suggested its role in the repair of the DNA damage produced by ionizing radiation and temozolomide. However, TDP1 relevance has not yet been studied in glioma. Thus the aims of this project are to identify the role of TDP1 in glioma aggressiveness and resistance to therapies. We hypothesize that high-grade gliomas possess higher TDP1 levels which are associated with lower survival and resistance to therapy. Quantitative real-time PCR analysis of TDP1 in glioma biopsies revealed a negative prognostic effect of TDP1, where the level of TDP1 mRNA was inversely correlated with patient survival. Moreover, western blot showed an overexpression of TDP1 in glioma biopsies compared to normal tissues and increased expression with higher grades. TDP1 overexpression in U87 cell lines did not induce resistance to temozolomide, topotecan, etoposide or doxorubicin. This may be related to other downstream DNA repair enzymes that need to be also modulated to fully induce drug resistance. However, TDP1 inhibition using small molecules synergizes the cytotoxicity of topotecan, etoposide, and doxorubicin, confirming thus its critical role in response to several therapeutic agents. As a conclusion, TDP1 is a new and promising prognostic factor and a modulator of therapy response in malignant glioma that may help in stratification of patients. Additionally, targeting TDP1 is a novel strategy that will widen the therapeutic options for malignant glioma where topoisomerase I and II poisons can be part of the gold standard therapy when used in combination with TDP1 inhibitors. Citation Format: Maha Al-Keilani, Supreet Agarwal, Mohammad Alqudah, Zita Sibenaller, Timothy Ryken, Mahfoud Assem. Tyrosyl DNA phosphodiesterase I is a prognostic factor and its inhibition synergizes response to topoisomerase poisons in malignant glioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2194. doi:10.1158/1538-7445.AM2013-2194