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Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy

Tumor cells are particularly dependent on NAD(+) due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD(+) biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicit...

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Autores principales: Cole, Jonathan, Guiot, Marie-Christine, Gravel, Michel, Bernier, Cynthia, Shore, Gordon C., Roulston, Anne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652819/
https://www.ncbi.nlm.nih.gov/pubmed/29100430
http://dx.doi.org/10.18632/oncotarget.20840
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author Cole, Jonathan
Guiot, Marie-Christine
Gravel, Michel
Bernier, Cynthia
Shore, Gordon C.
Roulston, Anne
author_facet Cole, Jonathan
Guiot, Marie-Christine
Gravel, Michel
Bernier, Cynthia
Shore, Gordon C.
Roulston, Anne
author_sort Cole, Jonathan
collection PubMed
description Tumor cells are particularly dependent on NAD(+) due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD(+) biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD(+) biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression. Most normal tissues express NAPRT while a significant proportion of malignant cells do not, providing a possible selection marker for patients to achieve NAMPTi efficacy while minimizing toxicities. Here we identify and validate a novel highly NAPRT-specific monoclonal antibody (3C6D2) that detects functional NAPRT in paraffin embedded tissue sections by immunohistochemistry (IHC). NAPRT detection by 3C6D2 coincides with the ability of niacin to rescue cells from NAMPTi induced cytotoxicity in cell lines and animal xenograft models. 3C6D2 binds to an epitope that is unique to NAPRT among phosphoribosyltransferases. In a series of primary tumor samples from lung and brain cancer patients, we demonstrate that >70 % of human small cell lung carcinomas, glioblastomas and oligodendrogliomas lack NAPRT identifying them as potentially suitable indications for the NAMPT/niacin combination.
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spelling pubmed-56528192017-11-02 Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy Cole, Jonathan Guiot, Marie-Christine Gravel, Michel Bernier, Cynthia Shore, Gordon C. Roulston, Anne Oncotarget Research Paper Tumor cells are particularly dependent on NAD(+) due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD(+) biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD(+) biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression. Most normal tissues express NAPRT while a significant proportion of malignant cells do not, providing a possible selection marker for patients to achieve NAMPTi efficacy while minimizing toxicities. Here we identify and validate a novel highly NAPRT-specific monoclonal antibody (3C6D2) that detects functional NAPRT in paraffin embedded tissue sections by immunohistochemistry (IHC). NAPRT detection by 3C6D2 coincides with the ability of niacin to rescue cells from NAMPTi induced cytotoxicity in cell lines and animal xenograft models. 3C6D2 binds to an epitope that is unique to NAPRT among phosphoribosyltransferases. In a series of primary tumor samples from lung and brain cancer patients, we demonstrate that >70 % of human small cell lung carcinomas, glioblastomas and oligodendrogliomas lack NAPRT identifying them as potentially suitable indications for the NAMPT/niacin combination. Impact Journals LLC 2017-09-12 /pmc/articles/PMC5652819/ /pubmed/29100430 http://dx.doi.org/10.18632/oncotarget.20840 Text en Copyright: © 2017 Cole et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cole, Jonathan
Guiot, Marie-Christine
Gravel, Michel
Bernier, Cynthia
Shore, Gordon C.
Roulston, Anne
Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title_full Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title_fullStr Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title_full_unstemmed Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title_short Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
title_sort novel naprt specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a nampt inhibitor/niacin co-administration strategy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652819/
https://www.ncbi.nlm.nih.gov/pubmed/29100430
http://dx.doi.org/10.18632/oncotarget.20840
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