Targeting IL-13Rα2 in human pancreatic ductal adenocarcinoma with combination therapy of IL-13-PE and gemcitabine
Targeting IL-13Rα2 in human pancreatic ductal adenocarcinoma with combination therapy of IL-13-PE and gemcitabine
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DOI：
10.1002/ijc.25437
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发表时间：
2011-03-01
影响因子：
6.4
通讯作者：
Puri, Raj K.
中科院分区：
文献类型：
--
作者：
Fujisawa, Toshio;Nakashima, Hideyuki;Puri, Raj K.
胰腺癌：癌症是一种侵袭性疾病，只有有限的治疗选择。我们已经确定71%的胰腺导管腺癌（PDA）表达高水平的IL-13 R α 2，一种IL-13的高亲和力受体。为了靶向IL-13 R α 2，我们已经开发了重组免疫毒素，其是IL-13和假单胞菌外毒素（IL-13-PE）的融合物。由于IL-13-PE和常用的细胞毒性药物吉西他滨通过不同的机制起作用，我们假设它们在介导抗肿瘤反应中协同作用。IL-13-PE和吉西他滨均介导对两种胰腺癌细胞系的细胞毒性，并且当组合时观察到协同细胞毒性。这种协同作用也在人PDA的原位小鼠模型中得到了体内证实。IL-13-PE和吉西他滨显示出在早期癌症模型中57%的小鼠中通过GFP转染的肿瘤的全身成像评估的肿瘤的完全放射，导致存活期的延长。相比之下，单用任何一种药物都不能产生完全的放射，但肿瘤体积显著减小。在晚期PDA模型中，与单独使用任一种药物治疗的动物相比，联合治疗也显著减少了肿瘤生长并提高了存活率。当在肿瘤植入之前通过RNAi敲低IL-13 R α 2时，IL-13-PE和吉西他滨不协同作用，表明IL-13 R α 2是必需的。从机制上讲，吉西他滨在体外和体内增加了IL-13 R α 2的表达，这导致了联合治疗的协同作用。有趣的是，PDA癌干细胞对吉西他滨耐药，但对IL-13-PE不耐药。这些结果表明，IL-13-PE和吉西他滨联合治疗可能是PDA治疗的一种有用策略。
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-13R alpha 2, a high-affinity receptor for IL-13. To target IL-13R alpha 2, 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-13R alpha 2 was knocked-down by RNAi prior to tumor implantation, IL-13-PE and gemcitabine did not synergize indicating that IL-13R alpha 2 is essential. Mechanistically, gemcitabine increased IL-13R alpha 2 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.