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Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)), which is a vital cofactor in redox reactions and a substrate for NAD(+) consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been...

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Autores principales: Davis, Katelynn, Dunseth, Craig D., Mott, Sarah L., Cramer-Morales, Kimberly L., Miller, Ann M., Ear, Po Hien, Mezhir, James J., Bellizzi, Andrew M., Chan, Carlos H. F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411120/
https://www.ncbi.nlm.nih.gov/pubmed/30856230
http://dx.doi.org/10.1371/journal.pone.0213576
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author Davis, Katelynn
Dunseth, Craig D.
Mott, Sarah L.
Cramer-Morales, Kimberly L.
Miller, Ann M.
Ear, Po Hien
Mezhir, James J.
Bellizzi, Andrew M.
Chan, Carlos H. F.
author_facet Davis, Katelynn
Dunseth, Craig D.
Mott, Sarah L.
Cramer-Morales, Kimberly L.
Miller, Ann M.
Ear, Po Hien
Mezhir, James J.
Bellizzi, Andrew M.
Chan, Carlos H. F.
author_sort Davis, Katelynn
collection PubMed
description BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)), which is a vital cofactor in redox reactions and a substrate for NAD(+) consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been shown in various cancers and its inhibition decreases cancer cell growth, making it an attractive therapeutic target. Here we examine the NAMPT expression in a large cohort of resected stage I/II pancreatic ductal adenocarcinomas (PDAs) and correlate its expression with clinical outcomes and pathologic features. METHODS: A retrospective review of patients with PDAs was conducted at a single institution. Tissue microarrays (TMAs) containing primary PDAs and their metastatic lymph nodes (mLNs) were constructed and stained for NAMPT expression. Each TMA core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong) and a mean score was calculated for each case with at least two evaluable cores. NAMPT expression was correlated with clinicopathological variables using chi-squared or Fisher’s exact test, and t-tests for categorical and continuous variables, respectively. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox proportional hazards regression was used to assess the effects of NAMPT staining values on recurrence-free survival (RFS) and overall survival (OS). This study was conducted under an approved IRB protocol. RESULTS: 173 primary PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.55 (range: 0 to 2.33). The mean IHC score of mLNs was 0.39 (range: 0–2), which was not significantly different from their primary tumors (mean IHC score = 0.47, P = 0.38). Sixty-four percent (111/173) of PDAs were positive for NAMPT staining. Stage II tumors were more likely to be positive (68% of 151 vs 41% of 22; P = 0.01). Non-obese non-diabetic patients were more likely to have NAMPT+ tumors (43.7% vs. 27.9%, P = 0.04). While RFS and OS were not statistically different between NAMPT+ vs. NAMPT- PDAs, patients with NAMPT- tumors tended to have a longer median OS (26.0 vs. 20.4 months, P = 0.34). CONCLUSION: NAMPT expression was detected in 64% of stage I/II PDAs and up to 72% in non-obese non-diabetic patients. Frequency of NAMPT expression correlated with pathological stage, consistent with published literature regarding its role in cancer progression. While RFS and OS were not statistically significantly different, patients with NAMPT+ PDAs tended to have a shorter survival. Thus, NAMPT inhibition may prove beneficial in clinical trials.
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spelling pubmed-64111202019-04-01 Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma Davis, Katelynn Dunseth, Craig D. Mott, Sarah L. Cramer-Morales, Kimberly L. Miller, Ann M. Ear, Po Hien Mezhir, James J. Bellizzi, Andrew M. Chan, Carlos H. F. PLoS One Research Article BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)), which is a vital cofactor in redox reactions and a substrate for NAD(+) consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been shown in various cancers and its inhibition decreases cancer cell growth, making it an attractive therapeutic target. Here we examine the NAMPT expression in a large cohort of resected stage I/II pancreatic ductal adenocarcinomas (PDAs) and correlate its expression with clinical outcomes and pathologic features. METHODS: A retrospective review of patients with PDAs was conducted at a single institution. Tissue microarrays (TMAs) containing primary PDAs and their metastatic lymph nodes (mLNs) were constructed and stained for NAMPT expression. Each TMA core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong) and a mean score was calculated for each case with at least two evaluable cores. NAMPT expression was correlated with clinicopathological variables using chi-squared or Fisher’s exact test, and t-tests for categorical and continuous variables, respectively. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox proportional hazards regression was used to assess the effects of NAMPT staining values on recurrence-free survival (RFS) and overall survival (OS). This study was conducted under an approved IRB protocol. RESULTS: 173 primary PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.55 (range: 0 to 2.33). The mean IHC score of mLNs was 0.39 (range: 0–2), which was not significantly different from their primary tumors (mean IHC score = 0.47, P = 0.38). Sixty-four percent (111/173) of PDAs were positive for NAMPT staining. Stage II tumors were more likely to be positive (68% of 151 vs 41% of 22; P = 0.01). Non-obese non-diabetic patients were more likely to have NAMPT+ tumors (43.7% vs. 27.9%, P = 0.04). While RFS and OS were not statistically different between NAMPT+ vs. NAMPT- PDAs, patients with NAMPT- tumors tended to have a longer median OS (26.0 vs. 20.4 months, P = 0.34). CONCLUSION: NAMPT expression was detected in 64% of stage I/II PDAs and up to 72% in non-obese non-diabetic patients. Frequency of NAMPT expression correlated with pathological stage, consistent with published literature regarding its role in cancer progression. While RFS and OS were not statistically significantly different, patients with NAMPT+ PDAs tended to have a shorter survival. Thus, NAMPT inhibition may prove beneficial in clinical trials. Public Library of Science 2019-03-11 /pmc/articles/PMC6411120/ /pubmed/30856230 http://dx.doi.org/10.1371/journal.pone.0213576 Text en © 2019 Davis et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Davis, Katelynn
Dunseth, Craig D.
Mott, Sarah L.
Cramer-Morales, Kimberly L.
Miller, Ann M.
Ear, Po Hien
Mezhir, James J.
Bellizzi, Andrew M.
Chan, Carlos H. F.
Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title_full Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title_fullStr Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title_full_unstemmed Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title_short Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma
title_sort nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage i/ii pancreatic ductal adenocarcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411120/
https://www.ncbi.nlm.nih.gov/pubmed/30856230
http://dx.doi.org/10.1371/journal.pone.0213576
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