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
Targeted Therapy
DOI:
10.1158/1078-0432.c.6526734.v1
Publication Date:
2023-04-01T06:27:53Z
AUTHORS (25)
ABSTRACT
<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>
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