Improving the Efficacy and Expanding the Application of NQO1-Bioactivated Therapeutics




Moore, Zachary Ray

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NADPH:quinone oxidoreductase-1 (NQO1)-bioactivated drugs, such as ß-lapachone (ß-lap), are powerful therapeutics for tumor-specific therapy. They react with NQO1, which is highly overexpressed in most solid tumors, to cause a futile redox cycle that results in devastating oxidative DNA damage and energy depletion in the form of ATP, NAD(H) and NADP(H) loss specifically in tumor cells. However, ß-lap suffers from inherent limitations shared by quinone therapeutics, most notably methemoglobinemia at high doses caused by non-specific oxidation of hemoglobin. My goal was to increase the efficacy of ß-lap at lower, well-tolerated doses without increasing normal tissue toxicity. Targeting the NAD+ synthesis pathway by inhibiting NAMPT prevented cells from surviving the metabolic stress of NAD+ and ATP depletion induced by PARP1 hyperactivation secondary to ß-lap treatment. This resulted in synergistic cancer cell death at normally sublethal doses of both ß-lap and NAMPT inhibitors, occurring through the same NAD+-Keresis mechanism as with ß-lap alone. On the other hand, synergy with PARP inhibitors occurred due to an increased accumulation of DNA double strand breaks, which was a result of inhibited repair of ß-lap-induced single strand breaks. In contrast to synergy observed with NAMPT inhibition, PARP inhibitors combined with ß-lap caused canonical caspase-mediated apoptosis. In addition to providing new treatments for further preclinical and clinical development, these studies elucidated the importance of NAD+ and ATP depletion in cell death induced by ß-lap. Furthermore, these treatment strategies increase the tumor specificity and widen the use of both NAMPT and PARP inhibitors, since in combination with ß-lap they are effective against all NQO1-overexpressing tumor cells. As a study in expanding the application of NQO1-bioactivated therapeutics, I have also demonstrated NQO1 overexpression and ß-lap sensitivity in atypical teratoid rhaboid tumors (ATRTs), a rare but deadly pediatric malignancy that can be targeted with NQO1-bioactivated therapeutics.

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