Abstract B047: A novel and efficient therapeutic strategy to target β1 integrin in metastatic cells from different cancer types

Purpose: We aim to develop new therapeutic strategies to control advanced metastatic disease in cancer. We hypothesized that targeting α2β1 integrin activation with cadherin RGD blocking monoclonal antibodies is an efficient procedure to reduce metastatic spread in multiple tumors. Experimental Procedures: Monoclonal antibodies (mAbs) were generated against a 9-mer peptide containing the RGD motif and flanking sequences of CDH17 (aka LI-cadherin). Antibodies were tested for inhibition of β1 integrin activation, cell adhesion, proliferation and invasion assays using cell lines from different cancer types (KM12SM (colorectal), PANC1 (pancreatic), BLM (melanoma,) and MDA-MB-468 (breast)) expressing CDH17 and VE-cadherin. The impact of the CDH RGD-specific mAbs on cell signaling was assessed by Western blot. Swiss nude mice were used to generate liver and lung metastasis with colorectal and melanoma cancer cell lines. Results: CDH RGD-specific mAbs were prepared and characterized. They recognized CDH17 and VE-cadherin positive cells by immunoprecipitation, flow cytometry, and confocal microscopy. CDH RGD mAbs blocked β1 integrin activation in metastatic cancer cell lines from different cancer types, causing a significant reduction in cell adhesion and proliferation. Signaling events related with FAK, JNK, ERK, Src, and AKT phosphorylation were blocked by the mAbs at different extent, according to the cancer type. Finally, CDH RGD mAbs caused a significant and persistent survival in nude mice developing lung and liver metastasis after intravenous or intrasplenic cell inoculation. Conclusions: CDH RGD mAbs constitute a promising therapy to control metastatic spread in colorectal cancer, melanoma, and probably other tumors expressing CDH17, VE-cadherin, or related RGD cadherins. Citation Format: Ignacio Casal, Ruben A. Bartolome, Marta Jaen, Carmen Aizpurua, Eva Calvino, Juan I. Imbaud. A novel and efficient therapeutic strategy to target β1 integrin in metastatic cells from different cancer types [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B047.