Doctor of Philosophy (PhD)
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glioblastoma, topoisomerase, tyrosyl-DNA phosphodiesterase
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Glioblastoma (GBM) patients have an estimated survival of ~15 months, with the standard of care (surgery, radiation, and chemotherapy) that has only modestly enhanced patient survival. Identifying biomarkers representing vulnerabilities in GBM biology may allow for the selection of effective and safe chemotherapy options. Irinotecan (IRT), a genotoxic compound currently in clinical trials for GBM, targets topoisomerase I (TOP1) by forming an irreversible ternary DNA-TOP1 cleavage complex (TOP1cc) and leads to apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that rescues TOP1cc and reduces the effectiveness of IRT. In the current study, we evaluate the value of the TDP1/TOP1 activity ratio as a prospective biomarker for the personalized use of IRT on GBM patients.
After analysis of susceptibility of nine GBM cell lines to IRT treatment along with TDP1 and TOP1 expression and activity levels in these cell lines, we found that the TDP1/TOP1 activity ratio had the strongest correlation (R=0.972, P=1.2×10-5) with IRT IC50values for a decrease of cell viability following IRT treatment. Increasing the TDP1/TOP1 activity ratio by ectopic expression of wild-type TDP1 increased in IRT IC50, while expression of the TDP1 catalytic-null mutant did not alter the susceptibility to IRT. Further, after analyzing GBM patient tumors, TDP/TOP1 activity ratio was found to correlate (R=-0.707, P=0.03) with patient survival significantly. Correlations were also observed between patient age and survival this set of GBM patients (R=-0.929, P=0.023) as well as GBM patients in the TCGA database (R=-0.353, P=7.7×10-17).
From our results, we suggested that the TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to IRT, which may allow for the selection of individual patients for IRT treatment based on risk-benefit. As a predictor, the lower TDP1/TOP1 activity ratio would correspond to higher IRT cytotoxicity. In addition, TDP1/TOP1 activity ratio might be a potential prognostic indicator for GBM patient survival. The lower TDP1/TOP1 ratio would correspond to patients with longer survival probability. Finally, inhibitors of TDP1 may be useful for novel combination therapy with IRT to improve GBM patient responsiveness to genotoxic chemotherapies.
Wang, Wenjie, "Topoisomerase and Tyrosyl-DNA-phosphodiesterase Ratio as an Indicator for the Response of Glioblastoma Cancer to Topoisomerase Targeting Anticancer Drugs" (2019). FIU Electronic Theses and Dissertations. 4254.
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