title: Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.
abstract: With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.
authors.affiliation: Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA. pmukherj@uncc.edu
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Gargi D
authors.initials: GD
authors.lastname: Basu
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Tinder
authors.forename: Durai B
authors.initials: DB
authors.lastname: Subramani
authors.forename: Judy M
authors.initials: JM
authors.lastname: Bradley
authors.forename: Million
authors.initials: M
authors.lastname: Arefayene
authors.forename: Todd
authors.initials: T
authors.lastname: Skaar
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Petris
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000906:Antibodies / Q000097:blood; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000008:administration & dosage / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000906:Antibodies; D019496:Cancer Vaccines; D052246:Cyclooxygenase 2 Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C060192:MUC1 protein, human; D018396:Mucin-1; D011720:Pyrazoles; D013449:Sulfonamides; D022223:Vaccines, Subunit; D003841:Deoxycytidine; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D000093542:Gemcitabine