Clinical Cancer Research, 2017 June
Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies: a major breakthrough for K-RAS mutated colorectal cancer treatment
Alexandre Prieur, Monica Cappellini, Guillaume Habif, Marie-Paule Lefranc, Thibault Mazard, Eric Morency, Jean-Marc Pascussi, Maud Flaceliere, Nathalie Cahuzac, Berengere Vire, Benjamin Dubuc, Amandine Durochat, Pierre Liaud, Jérémy Ollier, Caroline Pfeiffer, Sophie Poupeau, Véronique Saywell, Chris Planque, Eric Assenat, Frédéric Bibeau, Jean-François Bourgaux, Pascal Pujol, Alain Sézeur, Marc Ychou and Dominique Joubert.
Patients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct b-catenin/Tcf4 target gene. In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling, CSCs and reduce relapses.
We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of CRC cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.
All together, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS mutated colorectal patients, for which there is a crucial unmet medical need.