Data from Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer

• DOI: 10.1158/1078-0432.c.6526734.v1
• Publication Date: 2023-04-01T06:27:53Z
• Authors: Alexandre Prieur; Monica Cappellini; Guillaume Habif; Marie-Paule Lefranc; Thibault Mazard; Eric Morency; Jean-Marc Pascussi; Maud Flacelière; Nathalie Cahuzac; Bérengère Vire; Benjamin Dubuc; Amandine Durochat; Pierre Liaud; Jérémy Ollier; Caroline Pfeiffer; Sophie Poupeau; Véronique Saywell; Chris Planque; Eric Assenat; Frédéric Bibeau; Jean-François Bou...; Pascal Pujol; Alain Sézeur; Marc Ychou; Dominique Joubert

<div>Abstract<p><b>Purpose:</b> Patients with metastatic colorectal cancer 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 β-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.</p><p><b>Experimental Design:</b> Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed <i>in vitro</i> and <i>in vivo</i>, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.</p><p><b>Results:</b> We show that anti-progastrin antibodies decrease self-renewal of CSCs both <i>in vitro</i> and <i>in vivo</i>, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity <i>in vitro</i> 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.</p><p><b>Conclusions:</b> Altogether, 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. <i>Clin Cancer Res; 23(17); 5267–80. ©2017 AACR</i>.</p></div>