Abstract 4177: An IL13Rα2 peptide inhibits colorectal cancer metastatic progression

Abstract

Abstract Interleukin 13 receptor α2 (IL13Rα2) is an excellent tumoral marker for metastatic colorectal cancer and glioblastoma. Our goal was to block IL-13 binding to IL13Rα2 by using IL13Rα2 synthetic peptides in order to delay or suppress metastatic spread and progression. Peptides were selected from the D1 binding region. Synthetic peptides were synthesized using solid phase chemistry. Two metastatic colorectal cancer cell lines (KM12SM and SW620) plus two glioblastoma cell lines were used for testing proliferation, adhesion, migration and invasion. We used Biacore assays to demonstrate direct interaction between the peptides and IL-13. In vivo experiments with nude mice were performed to study mice survival to metastasis after peptide treatment. Peptides containing the highly preserved WKTIITKN motif of the D1 binding domain of IL13Rα2 demonstrated a strong capacity to inhibit migration, invasion and proliferation in metastatic colorectal cancer and glioblastoma cells. Alanine scanning experiments indicated that, at least, residues 82K, 83T, 85I and 86T were essential for IL-13 binding to IL13Rα2. IL13Rα2 D1 peptide inhibited IL-13-mediated cell signaling through FAK, Src, AKT and ERK1/2 in colorectal cancer and glioblastoma cell lines. Moreover, the D1 peptide abolished ligand-mediated receptor internalization and degradation. To improve bioavailability and resistance to proteolytic digestion for in vivo administration, we prepared the D enantiomer version of the peptide. Mice inoculated with metastatic colorectal cancer cells and treated with the enantiomer version of the D1 peptide showed a remarkable increase in survival. In conclusion, the D1 enantiomer peptide blocked the IL-13/IL13Rα2 binding, paving the way to develop novel and promising therapeutic strategies to inhibit metastatic progression in colorectal cancer and other solid tumors, including glioblastoma. Citation Format: Ignacio Casal, Marta Jaén, Rubén A. Bartolomé. An IL13Rα2 peptide inhibits colorectal cancer metastatic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4177.