Targeting IL-13Rα2 in human pancreatic ductal adenocarcinoma with combination therapy of IL-13-PE and gemcitabine.
Pancreatic cancer is an aggressive disease with only limited therapeutic options available. We have identified that 71% pancreatic ductal adenocarcinoma (PDA) express high levels of IL-13Rα2, a high-affinity receptor for IL-13. To target IL-13Rα2, we have developed a recombinant immunotoxin, which is a fusion of IL-13 and Pseudomonas exotoxin (IL-13-PE). Since IL-13-PE and a commonly used cytotoxic drug gemcitabine act by a different mechanism, we hypothesized that they synergize in mediating antitumor response. Both IL-13-PE and gemcitabine-mediated cytotoxicity to two pancreatic cancer cell lines and when combined synergistic cytotoxicity was observed. This synergism was also demonstrated in vivo in an orthotopic mouse model of human PDA. IL-13-PE and gemcitabine showed complete eradiation of tumors as assessed by whole body imaging of GFP-transfected tumors in 57% of mice in an early cancer model resulting into prolongation of survival. In contrast, monotherapy with either agent did not produce complete eradiation, but tumor volumes were significantly decreased. In advanced PDA model, combination therapy also produced dramatic reduction in tumor growth and enhanced survival compared to animals treated with either agent alone. When IL-13Rα2 was knocked-down by RNAi prior to tumor implantation, IL-13-PE and gemcitabine did not synergize indicating that IL-13Rα2 is essential. Mechanistically, gemcitabine increased IL-13Rα2 expression in vitro and in vivo, which resulted in a synergism of combination therapy. Interestingly, PDA cancer stem cells were resistant to gemcitabine, but not to IL-13-PE. These results suggest that combination therapy with IL-13-PE and gemcitabine may be a useful strategy for PDA therapy.
Fujisawa
Toshio
T
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, MD, USA.
Nakashima
Hideyuki
H
Nakajima
Atsushi
A
Joshi
Bharat H
BH
Puri
Raj K
RK
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018793:Interleukin-13 / Q000008:administration & dosage; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093542:Gemcitabine
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D003841:Deoxycytidine; D000093542:Gemcitabine