Date Published: March 11, 2019
Publisher: Public Library of Science
Author(s): Katelynn Davis, Craig D. Dunseth, Sarah L. Mott, Kimberly L. Cramer-Morales, Ann M. Miller, Po Hien Ear, James J. Mezhir, Andrew M. Bellizzi, Carlos H. F. Chan, Juri G. Gelovani.
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.
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.
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).
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.
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers in the United States, with a 5-year overall survival rate of 7% . While surgery is the only curative treatment, most patients are not surgical candidates due to late presentation and have cancer recurrence soon after surgery; hence, response to systemic chemotherapy dictates their overall survival. However, response rate remains poor with current standard systemic chemotherapy .
NAMPT is an attractive metabolic target for cancer treatment. Inhibition of NAMPT by specific inhibitors, such as FK866, or its down-regulation by siRNA reduces intracellular NAD+ level and decreases cancer cell growth in both in vitro and in vivo models [5, 7, 10, 11, 15]. Inhibition of NAMPT has also been shown to increase susceptibility to cellular oxidative stress and potentiate chemotherapeutic effect [9, 13, 16, 17]. However, NAMPT expression has not been well studied in human PDA with only one small study including 23 patient-derived pancreatic cancer cell lines . In our current study with 173 analyzable patients with PDAs on the TMAs constructed at the University of Iowa, NAMPT was expressed in 64% of PDAs and up to 72% of PDAs in non-obese non-diabetic patients. It is unclear why obese or diabetic patients have a lower incidence of NAMPT expression in PDA. Obese individuals can have elevated circulating levels of extracellular NAMPT derived from their adipose tissues . We have unpublished preliminary data showing elevated serum levels of NAMPT in obese and/or diabetic patients with pancreatic tumors. Similar observation has been demonstrated in obese patients with esophagogastric adenocarcinomas and breast cancer [8, 18]. We speculate that circulating NAMPT may exert a negative feedback on intracellular NAMPT expression, although further studies are required to examine such effect and to determine the underlying mechanism.