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HuR Status is a Powerful Marker for Prognosis and Response to Gemcitabine-Based Chemotherapy for Resected Pancreatic Ductal Adenocarcinoma Patients

Richards, Nathan G. MD*; Rittenhouse, David W. MD*; Freydin, Boris PhD†; Cozzitorto, Joseph A. BA*; Grenda, Dane BGS*; Rui, Hallgeir MD, PhD‡§; Gonye, Greg PhD¶; Kennedy, Eugene P. MD*§∥; Yeo, Charles J. MD*§∥; Brody, Jonathan R. PhD*§¶∥; Witkiewicz, Agnieszka K. MD*§¶∥

Annals of Surgery:
doi: 10.1097/SLA.0b013e3181f1fd44
Original Articles
Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is a devastating disease that killed nearly 38,000 people in the United States this past year.

Objective: Treatment of PDA typically includes surgery and/or chemotherapy with gemcitabine. No reliable biomarker exists for prognosis or response to chemotherapy. Two previously proposed prognostic markers, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), are regulated by Hu protein antigen R (HuR), an mRNA binding protein that we have previously demonstrated to be a promising predictive marker of gemcitabine response. This study was designed to evaluate the clinical utility of HuR, COX-2, and VEGF as potential prognostic and predictive biomarkers for PDA.

Methods: A tissue microarray of 53 PDA specimens from patients who underwent potentially curative pancreatic resection was analyzed. HuR, COX-2, and VEGF status were correlated with clinicopathologic and survival data. We also performed ribonucleoprotein immunoprecipitation assays using an HuR antibody to assess VEGF and COX-2 mRNA binding to HuR in pancreatic cancer cells.

Results: Roughly 50% (27/53) of patients had high cytoplasmic HuR expression. These patients had worse pathologic features as assessed by T staging (P = 0.005). Only cytoplasmic HuR status correlated with tumor T staging, whereas VEGF (P = 1.0) and COX-2 (P = 0.39) expression did not correlate with T staging. Additionally, HuR status was an unprecedented positive predictive marker for overall survival in patients treated with gemcitabine, pushing median survival over 45 months in the high cytoplasmic HuR expressing patient population compared with less than 23 months in the low cytoplasmic HuR expressing patient group (P = 0.033 for log-rank test and P = 0.04 in a Cox regression model) for the low versus high cytoplasmic HuR expressing group. We also validated that mRNA transcripts for both VEGF and the gemcitabine metabolizing enzyme, deoxycytidine kinase, are specifically bound by HuR in pancreatic cancer cells.

Conclusions: HuR is a useful prognostic biomarker for PDA patients as indicated by its association with higher tumor T stage. Additionally, HuR status is a robust predictor of outcome for patients with resected PDA in the setting of adjuvant gemcitabine therapy. Finally, HuR binds to VEGF mRNA implying that HuR, in part, regulates VEGF expression in PDA. This study supports the notion that HuR status should be used by clinicians for the individualized treatment of PDA in the future.

In Brief

HuR (Hu protein antigen R) is an mRNA binding protein previously described as a predictive biomarker for selecting pancreatic ductal adenocarcinoma patients for gemcitabine-based therapy. In an independent, validating sample set, high HuR cytoplasmic expression strongly correlated with patients' response to gemcitabine, and cytoplasmic HuR status correlated with adverse pathologic characteristics of pancreatic ductal adenocarcinoma better than vascular endothelial growth factor and cyclooxygenase-2. This study supports the notion that cytoplasmic HuR status can help guide the treatment of pancreatic ductal adenocarcinoma.

Author Information

From the Departments of *Surgery, †Pharmacology and Experimental Therapeutics, and ‡Cancer Biology, Thomas Jefferson University, Philadelphia, PA; §Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; ¶Department of Pathology, Thomas Jefferson University, Philadelphia, PA; and ∥The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA.

J.R.B. and A.K.W. contributed equally to the work in this manuscript.

This work was supported, in part, by a Grant #IRG-08-060-01 from the American Cancer Society [J.R.B.]; a PanCAN Career development Award, AACR [J.R.B.]; Fund A Cure for Pancreatic Cancer (Newtown, PA); American Cancer Society Research Scholar Award, RSG [J.R.B., A.K.W., J.A.C., and D.R.].

Reprints: Jonathan R. Brody, PhD, Department of Surgery, Thomas Jefferson University, Curtis 611-A, 1015 Walnut Street, Philadelphia, PA 19107. E-mail: jonathan.brody@jefferson.edu.

© 2010 Lippincott Williams & Wilkins, Inc.