Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model

Vallera, Daniel A.; Stish, B.J.; Shu, Yanqun; Chen, Hua; Saluja, Ashok K.; Buchsbaum, Donald J.; Vickers, Selwyn M.

doi:10.1136/gut.2007.137802

Cited by 23 publications

(22 citation statements)

References 40 publications

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“…A bispecific cytotoxin targeting receptors for epidermal growth factor and human IL-13 is shown to be effective in animal model of pancreatic cancer (13). IL-13 plays a central role in inflammation and immune responses and binds to two receptor subunits, IL-13Rα1 and IL-13Rα2 (14).…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

et al. 2009

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Whereas interleukin-13 receptor α2 chain (IL-13Rα2) is overexpressed in a variety of human solid cancers including pancreatic cancer, we investigated its significance in cancer invasion and metastasis. We used two pancreatic cancer cell lines, IL-13Rα2-negative HPAF-II and IL-13Rα2-positive HS766T, and generated IL-13Rα2 stably transfected HPAF-II as well as IL-13Rα2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13Rα2-negative and IL-13Rα2-positive cells and tumor metastasis was assessed in murine model for human pancreatic cancer with orthotopic implantation of tumors. IL-13 treatment enhanced cell invasion in IL-13Rα2-positive cancer cell lines but not in IL-13Rα2-negative cell lines. Furthermore, gene transfer of IL-13Rα2 in negative cell lines enhanced invasion, whereas its silencing downmodulated invasion of pancreatic cell lines in a Matrigel invasion assay. In vivo study revealed that IL-13Rα2-positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Rα2-negative tumors. The expression of IL-13Rα2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13Rα2-positive cancer displayed cachexia and poor prognosis. Invasion and metastasis also correlated with increased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13 activated extracellular signalregulated kinase 1/2 and activator protein-1 nuclear factors in IL-13Rα2-positive pancreatic cancer cell lines but not in IL-13Rα2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13Rα2 in pancreatic cancer cells and IL-13Rα2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

et al. 2009

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“…18,19 Recombinant cytotoxic fusion proteins carrying the enzymatically active portion of the DT and receptor-binding domains of IL-2 or of IL-3 have been successfully used in the treatment of T-cell lymphoma and acute myeloid leukemia in human beings. 20,21 An immunotoxin construct consisting of the vehicle, epidermal growth factor (EGF) and the toxin, DT, has been used for PC immunotoxin therapy in vitro, and in animal models, [22][23][24] as EGF receptor (EGFR) is known to be over-expressed in this tumor type. 25 However, EGFR expression by tissue, other than pancreatic tumor tissue, may cause nonspecific toxicity with side effects, such as fever, pain, hypoalbuminemia, increased transaminase levels and vascular leakage.…”

Section: Introductionmentioning

confidence: 99%

Heat-induced transcription of diphtheria toxin A or its variants, CRM176 and CRM197: implications for pancreatic cancer gene therapy

et al. 2009

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Vectors combining the heat shock proteins (HSPs) promoter with the catalytic subunit A of the diphtheria toxin (DTA) or its variants, cross-reacting material (CRM) 176 and 197, were engineered to investigate the effect of bacterial toxins on pancreatic cancer (PC) cells. Three heat-inducible enhanced green fluorescent protein (eGFP)-expression vectors were obtained: V1 (91% homology to HSPA6), V2 (five heat shock elements upstream the minimal HSPA6 promoter) and V3 (V1 and V2 combined). The highest eGFP transcription and translation levels were found in V3 transfected PC cells. The V3 promoter was used to control DTA, CRM176 and CRM197 expression, treatment response being investigated in four PC cell lines. DTAwt or CRM176 transfected cell growth was completely arrested after heat shock. CRM197 toxin presumed to be inactive, caused mild distress at 37 1C and induced a 25-50% reduction in cell growth after heat shock. Preliminary in vivo findings showed that heat treatment arrests tumor growth in DTA197 stably transfected PSN1 cells. In conclusion, the efficient HSP promoter identified in this study may be extremely useful in controlling the transcription of toxins such as CRM197, which have lethal dose-related effects, and may thus be a promising tool in PC gene therapy in vivo.

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“…Targeted toxins provide a unique opportunity for tumor therapy, offering an advantage of unique specificity and limiting potential toxicity to normal tissues. A bispecific cytotoxin that consists of Diptheria toxin, epidermal growth factor, and human IL-13 is shown to be effective in inducing tumor cell killing in vitro and in vivo against the MiaPaCa-2 cell line (20). Furthermore, IL-13PE38QQR and IL-4PE38QQR have also shown cytotoxic effects in some of the pancreatic cell lines in vitro (21).…”

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confidence: 99%

Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor α2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy

Shimamura

Fujisawa

Husain

et al. 2010

Clinical Cancer Research

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Purpose: Interleukin-13 receptor α2 (IL-13Rα2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13Rα2 in cancer.Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13Rα2 was examined by IL-13-induced signaling in pancreatic cancer cell lines. IL-13Rα2-positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer.Results: Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13Rα2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-β1 promoter activity in IL-13Rα2-positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2-negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13Rα2-positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample.Conclusions: These results indicate that IL-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-β activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Clin Cancer Res; 16(2); 577-86. ©2010 AACR.

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Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model

Cited by 23 publications

References 40 publications

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

Heat-induced transcription of diphtheria toxin A or its variants, CRM176 and CRM197: implications for pancreatic cancer gene therapy

Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor α2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy

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