Fiche publication
Date publication
septembre 2017
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BIBEAU Frédéric
Tous les auteurs :
Prieur A, Cappellini M, Habif G, Lefranc MP, Mazard T, Morency E, Pascussi JM, Flacelière M, Cahuzac N, Vire B, Dubuc B, Durochat A, Liaud P, Ollier J, Pfeiffer C, Poupeau S, Saywell V, Planque C, Assenat E, Bibeau F, Bourgaux JF, Pujol P, Sézeur A, Ychou M, Joubert D
Lien Pubmed
Résumé
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. 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 and , alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling. We show that anti-progastrin antibodies decrease self-renewal of CSCs both and , 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 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. 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. .
Mots clés
Animals, Antibodies, Anti-Idiotypic, administration & dosage, Antibodies, Monoclonal, Humanized, administration & dosage, Cell Proliferation, drug effects, Colorectal Neoplasms, drug therapy, Gastrins, antagonists & inhibitors, Gene Expression Regulation, Neoplastic, drug effects, HT29 Cells, Humans, Mice, Mutation, Neoplasm Recurrence, Local, drug therapy, Neoplastic Stem Cells, drug effects, Protein Precursors, antagonists & inhibitors, Proto-Oncogene Proteins p21(ras), genetics, Wnt Signaling Pathway, drug effects
Référence
Clin Cancer Res. 2017 Sep 1;23(17):5267-5280
