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Raj K. Puri - One of the best experts on this subject based on the ideXlab platform.
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Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between Interleukin-13 Receptor α1 and α2 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme
Journal of Neuro-Oncology, 2018Co-Authors: Jing Han, Raj K. PuriAbstract:Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 Receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2 ≥ 2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex ( IL-13Rα1 or IL-4Rα ) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM , etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.
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Analysis of Biodistribution of Intracranially Infused Radiolabeled Interleukin-13 Receptor–Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of
2016Co-Authors: Human Glioma, Bharat H. Joshi, Akiko Suzuki, Pamela Lel, Hisataka Kobayashi, Peter L. Choyke, Elaine M. Jagoda, Tomio Inoue, Raj K. PuriAbstract:for Interleukin-13 Receptor α2 (IL-13Rα2)–expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na125I and evaluated for its activity in vitro in Receptor-positive U251 or-negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantita-tively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125I-IL-13PE, which bound and was cytotoxic t
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analysis of biodistribution of intracranially infused radiolabeled Interleukin 13 Receptor targeted immunotoxin il 13pe by spect ct in an orthotopic mouse model of human glioma
The Journal of Nuclear Medicine, 2014Co-Authors: Akiko Suzuki, Bharat H. Joshi, Pamela Leland, Hisataka Kobayashi, Peter L. Choyke, Elaine M. Jagoda, Tomio Inoue, Raj K. PuriAbstract:Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for Interleukin-13 Receptor α 2( IL-13Rα2)–expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na 125 I and evaluated for its activity in vitro in Receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125 I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125I-IL-13PE, which bound and was cytotoxic to IL-13Rα2–positive but not to IL-13Rα2–negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of 125I-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CED administration produces a higher volume of distribution for a longer period of time than the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor.
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targeting of Interleukin 13 Receptor α2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of tgf β and pten signaling
Journal of Translational Medicine, 2013Co-Authors: Bradford Hall, Syed R. Husain, Raj K. Puri, Hideyuki Nakashima, Zhijun Sun, Yuki Sato, Yansong Bian, Ashok B KulkarniAbstract:Background The sixth leading class of cancer worldwide is head and neck cancer, which typically arise within the squamous epithelium of the oral mucosa. Human head and neck squamous cell carcinoma (HNSCC) is known to be difficult to treat and has only a 50% five-year survival rate. With HNSCC, novel therapeutics are needed along with a means of rapidly screening anti-cancer agents in vivo, such as mouse models.
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Interleukin 13 Receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma
Cancer, 2012Co-Authors: Meenu Jain, Raj K. Puri, Bharat H. Joshi, Lisa Zhang, Erin E Patterson, Naris Nilubol, Antonio Tito Fojo, Electron KebebewAbstract:Background Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options. Previous genome wide expression studies have shown overexpression of Interleukin-13 Receptor alpha2 (IL13Rα2) in some human malignancies.
Bharat H. Joshi - One of the best experts on this subject based on the ideXlab platform.
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Analysis of Biodistribution of Intracranially Infused Radiolabeled Interleukin-13 Receptor–Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of
2016Co-Authors: Human Glioma, Bharat H. Joshi, Akiko Suzuki, Pamela Lel, Hisataka Kobayashi, Peter L. Choyke, Elaine M. Jagoda, Tomio Inoue, Raj K. PuriAbstract:for Interleukin-13 Receptor α2 (IL-13Rα2)–expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na125I and evaluated for its activity in vitro in Receptor-positive U251 or-negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantita-tively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125I-IL-13PE, which bound and was cytotoxic t
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analysis of biodistribution of intracranially infused radiolabeled Interleukin 13 Receptor targeted immunotoxin il 13pe by spect ct in an orthotopic mouse model of human glioma
The Journal of Nuclear Medicine, 2014Co-Authors: Akiko Suzuki, Bharat H. Joshi, Pamela Leland, Hisataka Kobayashi, Peter L. Choyke, Elaine M. Jagoda, Tomio Inoue, Raj K. PuriAbstract:Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for Interleukin-13 Receptor α 2( IL-13Rα2)–expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na 125 I and evaluated for its activity in vitro in Receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125 I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125I-IL-13PE, which bound and was cytotoxic to IL-13Rα2–positive but not to IL-13Rα2–negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of 125I-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CED administration produces a higher volume of distribution for a longer period of time than the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor.
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Interleukin 13 Receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma
Cancer, 2012Co-Authors: Meenu Jain, Raj K. Puri, Bharat H. Joshi, Lisa Zhang, Erin E Patterson, Naris Nilubol, Antonio Tito Fojo, Electron KebebewAbstract:Background Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options. Previous genome wide expression studies have shown overexpression of Interleukin-13 Receptor alpha2 (IL13Rα2) in some human malignancies.
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specific targeting of human Interleukin il 13 Receptor α2 positive cells with lentiviral vectors displaying il 13
Human Gene Therapy Methods, 2012Co-Authors: Michael P Marino, Syed R. Husain, Raj K. Puri, Bharat H. Joshi, Akiko Suzuki, Andrea Maisner, Evanthia Galanis, Jakob ReiserAbstract:The ability to selectively and efficiently target transgene delivery to specific cell types in vitro and in vivo remains one of the formidable challenges in gene therapy. Lentiviral vectors have several advantages that make them attractive as gene delivery vehicles and their tropism can be altered through pseudotyping, allowing transgene delivery to specific populations of cells. The human Interleukin-13 Receptor α2 (IL-13Rα2) is uniquely overexpressed in many different human tumors, making it an attractive target for cancer therapy. In this study, we examined whether IL-13Rα2-positive tumor cells can be specifically targeted with lentiviral vector pseudotypes containing a truncated fusion (F) protein derived from measles virus (MV) and a tail-truncated and Receptor-blind MV hemagglutinin (H) protein bearing IL-13 at the C terminus. The retargeted lentiviral vector efficiently transduced cells that express high levels of IL-13Rα2, but not cells expressing low levels of IL-13Rα2 in vitro. In vivo, it specifically targeted IL-13Rα2-positive glioma cell xenografts in immunodeficient mice in the context of subcutaneous and intracranial glioma models. Similar lentiviral vectors may be developed for targeting other tumors expressing specific cell surface Receptors.
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Interleukin 13 mediates signal transduction through Interleukin 13 Receptor α2 in pancreatic ductal adenocarcinoma role of il 13 pseudomonas exotoxin in pancreatic cancer therapy
Clinical Cancer Research, 2010Co-Authors: Takeshi Shimamura, Syed R. Husain, Bharat H. Joshi, Toshio Fujisawa, Raj K. PuriAbstract: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
Koji Kawakami - One of the best experts on this subject based on the ideXlab platform.
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A novel Interleukin-13 Receptor alpha 2-targeted hybrid peptide for effective glioblastoma therapy.
Chemical biology & drug design, 2019Co-Authors: Ryohsuke Kurihara, Tomohisa Horibe, Eiko Shimizu, Aya Torisawa, Arong Gaowa, Masayuki Kohno, Koji KawakamiAbstract:We previously designed and reported a novel class of drugs, namely hybrid peptides, which are chemically synthesized and composed of a targeted binding peptide and a lytic-type peptide containing cationic amino acid residues that cause cancer cell death. In the present study, we screened for peptides that bind to Interleukin-13 Receptor alpha 2 (IL-13Rα2) by using a T7 random peptide phage display library system and isolated several positive phage clones. The A2b11 peptide, which was one of the positive clones, was shown to bind to IL-13Rα2 protein by Biacore analysis and a binding assay using glioblastoma (GB) cell lines. This peptide was linked with a lytic peptide containing a linker sequence to form the IL-13Rα2-lytic hybrid peptide. The IL-13Rα2-lytic hybrid peptide showed cytotoxic activity against GB cell lines in vitro. The IL-13Rα2-lytic hybrid peptide also affected Akt and Erk1/2 activation following treatment with Interleukin-13 and induced rapid ATP dynamics in GB cells. Anti-tumor activity of the IL-13Rα2-lytic hybrid peptide was observed in vivo after intratumoral injection in a mouse xenograft model of human GB cells. These results suggest that the IL-13Rα2-lytic hybrid peptide might be a potent therapeutic option for patients with GB.
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characterization of a novel human tumor antigen Interleukin 13 Receptor α2 chain
Cancer Research, 2006Co-Authors: Koji Kawakami, Mariko Kawakami, Masaki Terabe, Jay A. Berzofsky, Raj K. PuriAbstract:The Interleukin (IL)-13 Receptor α2 (IL-13Rα2) chain is a primary binding and internalization subunit for a Th2-derived immune regulatory cytokine, IL-13. Although extremely high levels of IL-13Rα2 chain are expressed on a variety of human tumor cells and specimens, its precise role in tumor immunology has not been defined. To investigate the role of IL-13Rα2 in tumor immunity, we used D5 melanoma cells stably transfected with the human IL-13Rα2 gene (D5α2) to assess the effect of an IL-13Rα2 DNA vaccine in immunocompetent animals. Prophylactic immunization of mice with the IL-13Rα2 DNA vaccine resulted in protection against D5α2 tumor development. In vivo depletion experiments in C57BL/6 and RAG-2 knockout mice indicated that both T and B cells, but not natural killer cells, were required for the tumor protection. In addition, antibody induced by the IL-13Rα2 DNA vaccine showed a modest but significant inhibitory effect on D5α2 cells in vitro , suggesting that the antibody is biologically functional. The IL-13Rα2 DNA vaccine also exhibited antitumor activity against established D5α2 tumors in mice. Histologic analysis of regressing tumors identified infiltration of CD4+ and CD8+ T cells and the expression of CXCL9 chemokine in tumors. Taken together, our results identify the human IL-13Rα2 chain as a novel tumor rejection antigen. (Cancer Res 2006; 66(8): 4434-42)
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analysis of Interleukin 13 Receptor α2 expression in human pediatric brain tumors
Cancer, 2004Co-Authors: Mariko Kawakami, Koji Kawakami, Satoru Takahashi, M Masato D Abe, Raj K. PuriAbstract:BACKGROUND Compared with normal brain tissue cells, human malignant glioma cells express higher levels of Interleukin-13 Receptor (IL-13R). However, whether this Receptor is expressed in situ has not been carefully examined. With IL-13R–targeted cytotoxin (IL13-PE38QQR, comprising IL-13 and a mutated form of Pseudomonas exotoxin [PE]) being tested in three Phase I/II clinical trials for the treatment of adult human glioma, and with pediatric studies being planned, the authors set out to analyze pediatric brain tumor tissue specimens for the expression of IL-13R. METHODS Using in situ hybridization and immunohistochemical staining, the authors examined 58 pediatric brain tumor specimens for expression of the predominant IL-13 binding and internalizing protein (IL-13Rα2) chain at the mRNA and protein levels. RESULTS Overall, approximately 83% of pediatric brain tumor samples expressed IL-13Rα2. One hundred percent (11 of 11) high-grade astrocytoma, 79% (26 of 33) low-grade astrocytoma, 67% (4 of 6) medulloblastoma, and 67% (2 of 3) ependymoma samples were positive for IL-13Rα2. Among IL-13Rα2–positive samples, 88% (42 of 48 samples) had positive expression in ≥ 50% of all tumor fields. The results obtained using both assays were consistent with each other. CONCLUSIONS The current study established that pediatric brain tumor specimens expressed the IL-13Rα2 chain. Because the IL-13Rα2 chain is a major binding component of the IL-13R complex, these results suggest that the targeting of IL-13R may represent a useful approach for the treatment of pediatric brain tumors. Cancer 2004. Published 2004 by the American Cancer Society.
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Interleukin 13 Receptor α2 chain in human head and neck cancer serves as a unique diagnostic marker
Clinical Cancer Research, 2003Co-Authors: Mariko Kawakami, Koji Kawakami, Jan L Kasperbauer, Lucinda Hinkley, Mamoru Tsukuda, Scott E Strome, Raj K. PuriAbstract:Previous studies have demonstrated that approximately 30% of squamous cell carcinoma of the head and neck (SCCHN) cell lines express high levels of Interleukin-13 Receptor(s) (IL-13R). However, the incidence, expression level, and significance of IL-13R expression in human tumor specimens is not known. In addition, it is not known whether normal head and neck tissues express IL-13R. In this study, we evaluated the expression of IL-13R subunits (IL-13Ralpha1, IL-13Ralpha2, and IL-4Ralpha) in 337 surgically excised specimens of SCCHN and normal head and neck tissues. Specimens were obtained from 139 patients with SCCHN and 16 patients with benign tonsil disorders from two centers in the United States and Japan and evaluated with immunohistochemistry and in situ hybridization. Extensive analysis demonstrated that the majority of SCCHN tumors uniformly expressed low levels of IL-13Ralpha1 chain; however, 77% of the tumors expressed moderate to high levels of IL-4Ralpha, which forms a signaling complex with IL-13Ralpha1 chain. On the other hand, 33% of SCCHN tumors expressed moderate to high levels of IL-13Ralpha2 chain. Using tissue array from 99 patients, we observed that the expression levels of IL-13Ralpha2 and IL-4Ralpha were significantly higher in SCCHN than in normal head and neck tissues (P < 0.005). Detailed analysis of clinicopathological features demonstrated a positive statistically significant correlation between IL-13Ralpha2 expression and clinically advanced primary SCCHN tumor (T(4); Tumor-Node-Metastasis classification; P < 0.05). However, there was no correlation among IL-13R expression and sex, age of patients, stage of lymph node metastasis, squamous cell carcinoma grade, or allergic history. Taken together, this study suggests that IL-13R may be involved in SCCHN tumor progression, and 33% of IL-13Ralpha2-positive SCCHN cases may be targeted by IL-13 cytotoxin and IL-13R-targeted agent.
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heterogeneity in Interleukin 13 Receptor expression and subunit structure in squamous cell carcinoma of head and neck differential sensitivity to chimeric fusion proteins comprised of Interleukin 13 and a mutated form of pseudomonas exotoxin
Clinical Cancer Research, 2002Co-Authors: Bharat H. Joshi, Koji Kawakami, Pamela Leland, Raj K. PuriAbstract:Squamous cell carcinoma of the head and neck (SCCHN) ischaracterized by a high proliferation index and marked propensity for local invasion resulting in poor prognosis for these patients. To develop tumor-targeted novel therapeutic agents, here we demonstrate that SCCHN cell lines express Receptors for an immune regulatory cytokine, Interleukin (IL) 13. By reverse transcription-PCR (RT-PCR), we found that 16 SCCHN cell lines express equally strong RT-PCR positive bands for mRNA of IL-13Rα1 and IL-4Rα chains. However, only three cell lines, HN12, YCUM911, and KCCT873, expressed a strong band for transcripts for IL-13Rα2 chain and five cell lines, YCUL891, KCCTC871, KCCL871, KCCTCM901, and RPMI 2650 expressed faint bands. Transcripts for IL-2Rγ c chain were absent in all of the cell lines tested. Indirect immunofluorescence analysis for four different Receptor chains confirmed RT-PCR results and showed pronounced expression of IL-13Rα2 protein in three high IL-13R expressing cell lines. All of the cell lines were equally positive for IL-13Rα1 and IL-4Rα chains. Receptor-binding studies demonstrated that IL-13Rα2-positive cell lines expressed a high density of IL-13 Receptors. Using two chimeric proteins composed of IL-13 and mutated forms of Pseudomonas exotoxin (IL-13-PE38 or IL-13-PE38QQR), we found that these two fusion toxins were highly and equally cytotoxic to IL-13Rα2-positive SCCHN, whereas IL-13Rα2-negative cell lines showed low or no sensitivity to IL-13 toxins. To additionally substantiate the critical role of the IL-13Rα2 chain in IL-13R-mediated cytotoxicity, two head and neck tumor cell lines (YCUMS861 and KB), devoid of the transcripts of this chain, were transfected with IL-13Rα2 cDNA and then tested for cytotoxicity. Transient transfection of the IL-13Rα2 chain highly sensitized these cells to IL-13 toxin as compared with mock-transfected control cells. Thus, our results indicate that IL-13Rα2 is present in 50% SCCHN tumor cell lines; of these, 19% are high expresser for this chain and respond to IL-13 cytotoxin. Thus, IL-13 cytotoxin may be a useful agent for high IL-13R-expressing SCCHN.
Pamela Leland - One of the best experts on this subject based on the ideXlab platform.
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analysis of biodistribution of intracranially infused radiolabeled Interleukin 13 Receptor targeted immunotoxin il 13pe by spect ct in an orthotopic mouse model of human glioma
The Journal of Nuclear Medicine, 2014Co-Authors: Akiko Suzuki, Bharat H. Joshi, Pamela Leland, Hisataka Kobayashi, Peter L. Choyke, Elaine M. Jagoda, Tomio Inoue, Raj K. PuriAbstract:Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for Interleukin-13 Receptor α 2( IL-13Rα2)–expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na 125 I and evaluated for its activity in vitro in Receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125 I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125I-IL-13PE, which bound and was cytotoxic to IL-13Rα2–positive but not to IL-13Rα2–negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of 125I-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CED administration produces a higher volume of distribution for a longer period of time than the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor.
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Overexpression of Interleukin-13 Receptor-α2 in Neuroendocrine Malignant Pheochromocytoma: A Novel Target for Receptor Directed Anti-Cancer Therapy
The Journal of clinical endocrinology and metabolism, 2009Co-Authors: Edwin W. Lai, Bharat H. Joshi, Toshio Fujisawa, Pamela Leland, Lucia Martiniova, Ritika Dogra, Ronald R. De Krijger, Irina A. Lubensky, Abdel G. Elkahloun, John C. MorrisAbstract:Context: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited. Objective: The objective of the study was to identify and characterize overexpression of IL-13 Receptor-α2 (IL-13Rα2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor’s response to a selective cytotoxin. Design/Setting/Patients: Expression of IL-13Rα2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR. Intervention: The function of IL-13Rα2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 μg/kg). Main Outcome M...
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human adrenomedullin up regulates Interleukin 13 Receptor alpha2 chain in prostate cancer in vitro and in vivo a novel approach to sensitize prostate cancer to anticancer therapy
Cancer Research, 2008Co-Authors: Bharat H. Joshi, Pamela Leland, Alfonso Calvo, Jeffrey Green, Raj K. PuriAbstract:Interleukin-13 (IL-13) Receptor alpha2 (IL-13Ralpha2), a high-affinity IL-13 binding subunit and a tumor antigen, is amplified in a variety of human tumor cell lines and tumors in vivo. By cDNA microarray, we have shown that gene transfer of human and rat adrenomedullin (AM) up-regulates IL-13Ralpha2 in a human prostate tumor cell line. Here, we show that IL-13Ralpha2 mRNA and protein are also up-regulated in PC-3 prostate tumor cells by recombinant AM (rAM) and human synthetic AM peptide in a dose-dependent manner in vitro and in vivo in mouse prostate tumor model. The 8- to 10-fold up-regulation of IL-13Ralpha2 by rAM or AM peptide in prostate tumor cells in vitro and in vivo increased their sensitivity to IL-13PE cytotoxin consisting of IL-13 and a truncated form of Pseudomonas exotoxin. Immunodeficient mice with established prostate tumors transfected with AM or treated with AM peptide showed reduction in tumor size by intratumoral administration of IL-13PE in a dose-dependent manner. At the highest dose (three 100 mug/kg/d every alternate day), >70% reduction of tumor size was observed compared with controls (P
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human adrenomedullin up regulates Interleukin 13 Receptor α2 chain in prostate cancer in vitro and in vivo a novel approach to sensitize prostate cancer to anticancer therapy
Cancer Research, 2008Co-Authors: Bharat H. Joshi, Pamela Leland, Alfonso Calvo, Jeffrey Green, Raj K. PuriAbstract:Interleukin-13 (IL-13) Receptor alpha2 (IL-13Ralpha2), a high-affinity IL-13 binding subunit and a tumor antigen, is amplified in a variety of human tumor cell lines and tumors in vivo. By cDNA microarray, we have shown that gene transfer of human and rat adrenomedullin (AM) up-regulates IL-13Ralpha2 in a human prostate tumor cell line. Here, we show that IL-13Ralpha2 mRNA and protein are also up-regulated in PC-3 prostate tumor cells by recombinant AM (rAM) and human synthetic AM peptide in a dose-dependent manner in vitro and in vivo in mouse prostate tumor model. The 8- to 10-fold up-regulation of IL-13Ralpha2 by rAM or AM peptide in prostate tumor cells in vitro and in vivo increased their sensitivity to IL-13PE cytotoxin consisting of IL-13 and a truncated form of Pseudomonas exotoxin. Immunodeficient mice with established prostate tumors transfected with AM or treated with AM peptide showed reduction in tumor size by intratumoral administration of IL-13PE in a dose-dependent manner. At the highest dose (three 100 mug/kg/d every alternate day), >70% reduction of tumor size was observed compared with controls (P
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Identification of Interleukin-13 Receptor α2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma
Neuro-oncology, 2008Co-Authors: Bharat H. Joshi, Mehmet Kocak, Rada A. Puri, Pamela Leland, Frederick Varricchio, Ghanshyam Gupta, Richard J. Gilbertson, Raj K. PuriAbstract:Human malignant glioma cell lines and adult brain tumors overexpress high levels of Interleukin-13 Receptor alpha2 chain (IL-13Ralpha2). Because the IL-13Ralpha2 chain is an important target for cancer therapy and prognosis for patients with brainstem glioma (BSG) remains dismal, we investigated the expression of this Receptor in specimens of diffusely infiltrative pediatric BSG relative to normal brain tissue. Twenty-eight BSG specimens and 15 normal brain specimens were investigated for IL-13Ralpha2 protein expression by immunohistochemical analysis (IHC) using two different antibodies in two different laboratories. Highly sensitive Q-dot-based IHC and in situ hybridization (ISH) assays were also developed to identify IL-13Ralpha2 protein and RNA in these specimens. The results were evaluated independently in two laboratories in a blinded fashion. By Q-dot IHC or a standard IHC assay, 17 of 28 (61%) tumor specimens showed modest to strong staining for IL-13Ralpha2, while 15 normal brain tissue samples showed weak expression for IL-13Ralpha2 protein. Significant interrater agreement between the two laboratories was seen in the assessment of IL-13Ralpha2 intensity. High-level IL-13Ralpha2 RNA expression was detected in tumor samples by Q-dot ISH, but only weak RNA expression was observed in normal brain. Significant agreement between ISH and IHC assays was observed (simple kappa [kappa] estimate=0.358, weighted kappa=0.89, p=0.001). IL-13Ralpha2 protein and mRNA are expressed to significantly higher levels in BSG than in normal brain tissue. Both IHC and ISH represent robust methods to detect expression of the IL-13Ralpha2 Receptor in BSG that could represent an important new drug target for treatment of this disease.
Syed R. Husain - One of the best experts on this subject based on the ideXlab platform.
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targeting of Interleukin 13 Receptor α2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of tgf β and pten signaling
Journal of Translational Medicine, 2013Co-Authors: Bradford Hall, Syed R. Husain, Raj K. Puri, Hideyuki Nakashima, Zhijun Sun, Yuki Sato, Yansong Bian, Ashok B KulkarniAbstract:Background The sixth leading class of cancer worldwide is head and neck cancer, which typically arise within the squamous epithelium of the oral mucosa. Human head and neck squamous cell carcinoma (HNSCC) is known to be difficult to treat and has only a 50% five-year survival rate. With HNSCC, novel therapeutics are needed along with a means of rapidly screening anti-cancer agents in vivo, such as mouse models.
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specific targeting of human Interleukin il 13 Receptor α2 positive cells with lentiviral vectors displaying il 13
Human Gene Therapy Methods, 2012Co-Authors: Michael P Marino, Syed R. Husain, Raj K. Puri, Bharat H. Joshi, Akiko Suzuki, Andrea Maisner, Evanthia Galanis, Jakob ReiserAbstract:The ability to selectively and efficiently target transgene delivery to specific cell types in vitro and in vivo remains one of the formidable challenges in gene therapy. Lentiviral vectors have several advantages that make them attractive as gene delivery vehicles and their tropism can be altered through pseudotyping, allowing transgene delivery to specific populations of cells. The human Interleukin-13 Receptor α2 (IL-13Rα2) is uniquely overexpressed in many different human tumors, making it an attractive target for cancer therapy. In this study, we examined whether IL-13Rα2-positive tumor cells can be specifically targeted with lentiviral vector pseudotypes containing a truncated fusion (F) protein derived from measles virus (MV) and a tail-truncated and Receptor-blind MV hemagglutinin (H) protein bearing IL-13 at the C terminus. The retargeted lentiviral vector efficiently transduced cells that express high levels of IL-13Rα2, but not cells expressing low levels of IL-13Rα2 in vitro. In vivo, it specifically targeted IL-13Rα2-positive glioma cell xenografts in immunodeficient mice in the context of subcutaneous and intracranial glioma models. Similar lentiviral vectors may be developed for targeting other tumors expressing specific cell surface Receptors.
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Interleukin 13 mediates signal transduction through Interleukin 13 Receptor alpha2 in pancreatic ductal adenocarcinoma role of il 13 pseudomonas exotoxin in pancreatic cancer therapy
Clinical Cancer Research, 2010Co-Authors: Takeshi Shimamura, Syed R. Husain, Toshio Fujisawa, Bharat Joshi, Raj K. PuriAbstract: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
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Interleukin 13 mediates signal transduction through Interleukin 13 Receptor α2 in pancreatic ductal adenocarcinoma role of il 13 pseudomonas exotoxin in pancreatic cancer therapy
Clinical Cancer Research, 2010Co-Authors: Takeshi Shimamura, Syed R. Husain, Bharat H. Joshi, Toshio Fujisawa, Raj K. PuriAbstract: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
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Interleukin 13 Receptor α2 chain
Cancer, 2006Co-Authors: Mitomu Kioi, Mariko Kawakami, Takeshi Shimamura, Syed R. Husain, Raj K. PuriAbstract:BACKGROUND Epithelial ovarian cancer demonstrates high mortality due to diagnosis at an advanced stage. In the search for a biomarker for early diagnosis and a target for therapy, the issue of whether Interleukin-13 Receptor (IL-13R), shown to be expressed on a variety of human cancers, is expressed in ovarian tumor samples was explored. In addition, whether this Receptor serves as a biomarker and can be targeted by IL-13 cytotoxin was examined. METHODS IL-13R expression in 15 normal and 68 ovarian tumor tissue samples was determined by immunohistochemistry. Correlation between clinicopathologic features and IL-13R expression was analyzed. The efficacy of IL-13R-directed cytotoxin was determined in mice with subcutaneous, orthotopic, and peritoneal metastatic ovarian cancer. RESULTS Immunohistochemical analyses revealed that 83% of ovarian cancer specimens express IL-13Rα2, a high-affinity IL-13R subunit chain, whereas normal ovary samples expressed none or very low levels. The majority of clear cell ovarian carcinomas with the worst prognosis showed strong staining for IL-13Rα2. IL-13 cytotoxin was highly cytotoxic to the IGROV-1 ovarian cancer cell line in vitro, and it mediated significant antitumor activity against a xenografted tumor model. The antitumor effects were confirmed by treating orthotopically implanted or peritoneal metastatic ovarian tumors, which showed significant extension of survival in immunodeficient mice. IL-13 cytotoxin also prevented cachexia in treated mice. The soluble form of IL-13Rα2 was detected in the serum of mice with peritoneal metastasis, and the level decreased to baseline in the treated group. CONCLUSIONS IL-13Rα2 is a promising target for ovarian cancer therapy, and the soluble form of IL-13R may be a possible surrogate marker for disease monitoring. Cancer. Published 2006 by the American Cancer Society.