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
• Keywords: Targeted Therapy

<div>Abstract<p><b>Purpose:</b> Patients with metastatic colorectal cancer suffer from disease relapse mainly due to stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal colon CSCs, which is also direct β-catenin/TCF4 target gene. In this study, we aimed develop novel targeted therapy neutralize secreted progastrin inhibit Wnt signaling, and reduce relapses.</p><p><b>Experimental Design:</b> Antibodies (monoclonal humanized) directed against were produced selected specificity affinity. After validation their effectiveness on survival cell lines harboring B-RAF or K-RAS mutations, efficacy was assessed <i>in vitro</i> vivo</i>, alone concomitantly chemotherapy, CSC capacity, tumor recurrence, signaling.</p><p><b>Results:</b> We show that anti-progastrin antibodies decrease CSCs both either in combination chemotherapy. Furthermore, migration invasion are diminished; chemosensitivity prolonged SW620 HT29 posttreatment significantly delayed T84 cells, xenografted nude mice. Finally, signaling activity decreased, and, transgenic mice developing Wnt-driven intestinal neoplasia, burden alleviated, amplification differentiation remaining tumors.</p><p><b>Conclusions:</b> Altogether, these data humanized might represent potential new treatment K-RAS–mutated patients, there crucial unmet medical need. <i>Clin Cancer Res; 23(17); 5267–80. ©2017 AACR</i>.</p></div>