Résumé
In metastatic colorectal cancer (CRC) patients, chemotherapy in combination with targeted therapies such as Avastin, Erbitux, and Vectibix (monoclonal antibodies) has improved response rates with prolongation of progression free survival and overall survival. Despite these major therapeutic progresses, at least 30 to 50% of patients remain non-responders.
Our project aimed to identify and validate new molecular targets of CRC. Comparison of gene expression profiles between normal mucosa and primary tumor of CRC patients followed by immunohistochemistry analysis identified claudin-1 (CLDN1) as potential therapeutic target for antibody-targeted therapy. CLDN1 is a major tight junction transmembrane protein, already found overexpressed in CRC in several studies and associated with tumor progression.
We have generated monoclonal antibodies (mAb) directed against extracellular domains of CLDN1 and demonstrated their specificity against human CLDN1 in vitro and in vivo. Then, using mice xenografted with the CRC cell line SW620 we tested the therapeutic effect of the 6F6C3mAb. The mice were treated by i.p. injections with vehicle or 6F6C3mAb at two different doses. The results showed that 6F6C3mAb treated-groups had a significant (p= 0,018) reduced growth compared to the control group and this effect was dose-dependent. The in vitro effects of the binding of 6F6C3mAb to CLDN1 were also assessed by clonogenic assays. Treatment by 6F6C3mAb induced a significant (p< 0.05) reduction of the number of colony-forming cells for CLDN1high colorectal cancer cells (SW620, Caco2) but also for CLDN1high ovarian and pancreatic cancer cells (PANC1, BXPC3, SKOV3, IGROV1). Thus, 6F6C3mAb binding had a profound effect on cancer cell survival.
In conclusion, CLDN1 seems to be a promising target for antibody-based therapy. The 6F6C3mAb is able to inhibit tumor growth and tumor survival by binding the extracellular domains of CLDN1. It can be used in the treatment of cancer diseases such as colorectal cancer as well in adjuvant as in metastatic setting.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B245.
Citation Format: Adeline Ayrolles-Torro, Nadia Vezzio-Vie, Vincent Denis, Florence Boissiere-Michot, Véronique Garambois, Muriel Busson, Imade Ait Arsa, Caroline Mollevi, Martine Pugniere, Frédéric Bibeau, Pierre Martineau, Céline Gongora, Maguy Del Rio. Claudin-1 (CLDN1) as a new therapeutic target in colorectal cancer: Inhibition of cell growth and survival by an anti-CLDN1 monoclonal antibody. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B245.