TDP2 as a biomarker of sensitivity to TOP2 targeting agents and as a novel therapeutic target

Ntai, Ioanna (2017) TDP2 as a biomarker of sensitivity to TOP2 targeting agents and as a novel therapeutic target. Doctoral thesis (PhD), University of Sussex.

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TDP2, a DNA phosphodiesterase that removes trapped topoisomerase 2 (TOP2) from 5’-DNA termini, is required for efficient repair of TOP2-induced DNA double-strand breaks (DSBs). Cellular depletion of TDP2 was shown to result in a substantially increased sensitivity to TOP2-induced DSBs and TOP2 poisons, such as etoposide, in various types of human cancer cell lines. In addition, over-expression of TDP2 has been shown to increase resistance to etoposide. Recent data suggest that expression levels of TDP2 vary greatly in different cancer cell lines. However, there are no reported studies addressing the possible role of TDP2 as a clinical predictor of anti-cancer therapy outcome, or wider studies correlating TDP2 over-expression with resistance to TOP2 poisons. TDP2 has the potential to be a good target for pharmacological inhibition potentially increasing tumour sensitivity to TOP2 poisons, particularly those that develop resistance during the course of treatment. There is already a lot of interest in the development of TDP2 inhibitors and the in vitro results are very promising with many possible small molecule inhibitors showing selectiveness in their target. In my thesis I aim to further establish the range of TDP2 and TOP2 mRNA and protein levels in a panel of lung and breast cancer cell lines. In addition, I will explore the possibility of a correlation between TDP2 protein levels or TOP2/TDP2 protein ratios and sensitivity to the TOP2 poison etoposide. This likely complex relationship will be further defined by possible mutation effects based on available literature and studies for the cancer cell lines accessible for this project. Furthermore, as etoposide has been tested in clinical trials not only alone but also in combination with other treatments, I aim to include other accessible drugs, either currently in use for cancer treatment or at a promising clinical trial stage, such as estradiol and PARP1 inhibitors.

There is a recent model, which suggests that induction of transcriptional programs by stimulating breast cancer cells with estrogens, or prostate cancer cells with androgens, can involve the formation of TOP2B mediated DSBs and the recruitment of DSB repair proteins. TOP2B is believed to be recruited with the estrogen/androgen receptor to regulatory sites on target genes. It is hypothesized that the formation of these DSBs by TOP2B could also be exploited therapeutically. In my thesis I aim to utilise a combination treatment that will first induce transcription with estradiol in breast cancer cells, which will cause transient TOP2B-mediated DSBs, and then transform those breaks into abortive breaks with etoposide. Cells will then be overwhelmed with DSBs and apoptosis will be promoted. This will also be explored in TDP2-depleted MCF7 breast cancer cells. Such a strategy could possibly find particular use in hormone dependent cancers, where other types of treatment have failed.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 01 Jun 2017 09:23
Last Modified: 01 Jun 2017 09:23

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