Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2017

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

Alexandre Prieur
  • Fonction : Auteur
Monica Cappellini
  • Fonction : Auteur
Guillaume Habif
  • Fonction : Auteur
Marie-Paule Lefranc
Eric Morency
  • Fonction : Auteur
Maud Flacelière
  • Fonction : Auteur
Bérengère Vire
  • Fonction : Auteur
Benjamin Dubuc
  • Fonction : Auteur
Amandine Durochat
  • Fonction : Auteur
Pierre Liaud
  • Fonction : Auteur
Jérémy Ollier
  • Fonction : Auteur
Caroline Pfeiffer
  • Fonction : Auteur
Sophie Poupeau
  • Fonction : Auteur
Véronique Saywell
  • Fonction : Auteur
Alain Sézeur
  • Fonction : Auteur
Dominique Joubert
  • Fonction : Auteur

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.Experimental Design: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 assessedin vitroandin vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.Results:We show that anti-progastrin antibodies decrease self-renewal of CSCs bothin vitroandin vivo, 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 activityin vitrois 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.Conclusions: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.Clin Cancer Res; 23(17); 5267-80. \textcopyright2017 AACR.

Dates et versions

hal-01760837 , version 1 (06-04-2018)

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Alexandre Prieur, Monica Cappellini, Guillaume Habif, Marie-Paule Lefranc, Thibault Mazard, et al.. Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer. Clinical Cancer Research, 2017, 23 (17), pp.5267--5280. ⟨10.1158/1078-0432.CCR-17-0533⟩. ⟨hal-01760837⟩
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