Abstract B15: Anti-metastatic activity of RGD-specific cadherin-17-targeting monoclonal antibodies in colorectal cancer

Abstract

Abstract Most colorectal cancer deaths occur as a consequence of late diagnosis and the appearance of metastasis. We demonstrated that a RGD motif present in liver-intestine cadherin, also known as cadherin 17 (CDH17), plays a critical role in the liver metastasis of colorectal cancer by interacting with α2β1 integrin. CDH17 is able to induce a conformational change in β1 integrin to promote a high affinity conformation. This change is dependent of the RGD motif present in domain 6 of CDH17. The same activation was observed after cell exposition to 9 amino acid peptides containing the RGD motif and the flanking sequences from CDH17. Commercial antibodies anti-CDH17 did not cause any effect on β1 integrin activation. Here, we have used peptides containing the RGD motif and their flanking sequences in CDH17 to retrieve four highly selective monoclonal antibodies with anti-metastatic activity. Only CDH17 RGD-specific monoclonal antibodies inhibited β1 integrin activation in colorectal cancer cells. This inhibition provoked a significant reduction in cell adhesion and proliferation of metastatic cells. In addition, the treatment with these four anti-cadherin RGD antibodies impaired the activation of FAK, JNK and ERK kinases, which are critical for cell adhesion and proliferation. Moreover, RGD-specific monoclonal antibodies were able to cause a significant increase in mouse survival after intra-splenic injection together with highly metastatic cells, as determined by Kaplan-Meier survival analysis and log-rank curves. However, this effect on survival was different for each monoclonal antibody, suggesting a relevant impact of the RGD binding orientation in antibody recognition. As a conclusion, we propose that blocking the interaction between RGD cadherins and α2β1 integrin with highly selective monoclonal antibodies constitutes a promising therapy against colon cancer progression and liver metastasis. Citation Format: Rubén Bartolomé, Sofia Torres, Beatriz Escudero-Paniagua, Carmen Aizpurua, Eva Calviño, Juan I. Imbaud, Ignacio Casal. Anti-metastatic activity of RGD-specific cadherin-17-targeting monoclonal antibodies in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B15.