Michela Capello1, Minhee Lee1, Hong Wang1, Ingrid Babel1, Matthew H Katz1, Jason B Fleming1, Anirban Maitra1, Huamin Wang1, Weihua Tian1, Ayumu Taguchi1, Samir M Hanash2. 1. : Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX (MC, HW, SMH); Fred Hutchinson Cancer Research Center, Seattle, WA (ML, IB); Departments of Surgical Oncology (MHK, JBF), Pathology (AM, HW, WT), and Translational Molecular Pathology (AM, HW, AT, SMH), The University of Texas MD Anderson Cancer Center, Houston, TX. 2. : Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX (MC, HW, SMH); Fred Hutchinson Cancer Research Center, Seattle, WA (ML, IB); Departments of Surgical Oncology (MHK, JBF), Pathology (AM, HW, WT), and Translational Molecular Pathology (AM, HW, AT, SMH), The University of Texas MD Anderson Cancer Center, Houston, TX. shanash@mdanderson.org.
Abstract
BACKGROUND: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. METHODS: CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided. RESULTS: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). CONCLUSION: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
BACKGROUND: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. METHODS:CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided. RESULTS: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). CONCLUSION: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
Authors: Tessa Ys Le Large; Giulia Mantini; Laura L Meijer; Thang V Pham; Niccola Funel; Nicole Ct van Grieken; Bart Kok; Jaco Knol; Hanneke Wm van Laarhoven; Sander R Piersma; Connie R Jimenez; G Kazemier; Elisa Giovannetti; Maarten F Bijlsma Journal: JCI Insight Date: 2020-08-06
Authors: Oliver H Wang; Nancy Azizian; Ming Guo; Michela Capello; Defeng Deng; Fenglin Zang; Jason Fry; Matthew H Katz; Jason B Fleming; Jeffrey E Lee; Robert A Wolff; Samir Hanash; Huamin Wang; Anirban Maitra Journal: PLoS One Date: 2016-03-29 Impact factor: 3.240