Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma
©2017 American Association for Cancer Research..
Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301-11. ©2017 AACR.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 23(2017), 23 vom: 01. Dez., Seite 7301-7311 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Heske, Christine M [VerfasserIn] |
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| Links: |
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| Themen: |
Cytokines |
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| Anmerkungen: |
Date Completed 16.07.2018 Date Revised 25.02.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-17-1121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM275708551 |
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| 100 | 1 | |a Heske, Christine M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma |
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| 500 | |a Date Revised 25.02.2020 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2017 American Association for Cancer Research. | ||
| 520 | |a Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301-11. ©2017 AACR | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
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| 700 | 1 | |a Davis, Mindy I |e verfasserin |4 aut | |
| 700 | 1 | |a Baumgart, Joshua T |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Kelli |e verfasserin |4 aut | |
| 700 | 1 | |a Gormally, Michael V |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaohu |e verfasserin |4 aut | |
| 700 | 1 | |a Ceribelli, Michele |e verfasserin |4 aut | |
| 700 | 1 | |a Duveau, Damien Y |e verfasserin |4 aut | |
| 700 | 1 | |a Guha, Rajarshi |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrer, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Arnaldez, Fernanda I |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Jiuping |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Huong-Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yiping |e verfasserin |4 aut | |
| 700 | 1 | |a Mendoza, Arnulfo |e verfasserin |4 aut | |
| 700 | 1 | |a Helman, Lee J |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Craig J |e verfasserin |4 aut | |
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