{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/8297"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/8297","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Improving the Efficacy and Expanding the Application of NQO1-Bioactivated Therapeutics","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Moore, Zachary Ray"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Brekken, Rolf A.","Boothman, David A.","Scaglioni, Pier Paolo","Gao, Jinming"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-06-02T21:01:55Z","date_published":"2020-06-02T21:01:55Z","updated_at":"2026-07-24T05:52:15Z","subjects":["NAD(P)H Dehydrogenase (Quinone)","Naphthoquinones","Neoplasms","Nicotinamide Phosphoribosyltransferase","Poly Adenosine Diphosphate Ribose"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1156324529"],"render_values":[{"text":"1156324529","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/8297","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Brekken, Rolf A.","Boothman, David A.","Scaglioni, Pier Paolo","Gao, Jinming"]},{"key":"dc:creator","label":"Author","values":["Moore, Zachary Ray"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2020-06-02T21:01:55Z","2018-05","2015-06-09","May 2018","2020-06-02T21:01:56Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["NAD(P)H Dehydrogenase (Quinone)","Naphthoquinones","Neoplasms","Nicotinamide Phosphoribosyltransferase","Poly Adenosine Diphosphate Ribose"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/8297","1156324529"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Improving the Efficacy and Expanding the Application of NQO1-Bioactivated Therapeutics"]}]}],"canonical_facts":{"dc:contributor":["Brekken, Rolf A.","Boothman, David A.","Scaglioni, Pier Paolo","Gao, Jinming"],"dc:creator":["Moore, Zachary Ray"],"dc:date":["2020-06-02T21:01:55Z","2018-05","2015-06-09","May 2018","2020-06-02T21:01:56Z"],"dc:description":["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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/8297","1156324529"],"dc:language":["en"],"dc:subject":["NAD(P)H Dehydrogenase (Quinone)","Naphthoquinones","Neoplasms","Nicotinamide Phosphoribosyltransferase","Poly Adenosine Diphosphate Ribose"],"dc:title":["Improving the Efficacy and Expanding the Application of NQO1-Bioactivated Therapeutics"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:15Z"}