title: Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma.
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).
  
  
  CONCLUSIONS
  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.affiliation: : 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.
authors.forename: Michela
authors.initials: M
authors.lastname: Capello
authors.affiliation: : 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.
authors.forename: Minhee
authors.initials: M
authors.lastname: Lee
authors.affiliation: : 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: : 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.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Babel
authors.affiliation: : 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.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: : 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.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: : 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.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: : 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.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: : 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.
authors.forename: Weihua
authors.initials: W
authors.lastname: Tian
authors.affiliation: : 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.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: : 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.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D043182:Carboxylesterase / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D018714:Radiotherapy, Adjuvant; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; D000077146:Irinotecan; C517204:CES2 protein, human; D043182:Carboxylesterase; D005472:Fluorouracil; D002166:Camptothecin