Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies: a major breakthrough for K-RAS mutated colorectal cancer treatment

Purpose: <p>Patients with metastatic colorectal cancer (CRC) 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 b-catenin/Tcf4 target gene. In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling, CSCs and reduce relapses.</p> Experimental Design: <p>Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of CRC cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSCs self-renewal capacity, tumor recurrence and Wnt signaling.</p> Results: <p>We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of CRC cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro 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> Conclusions:<br /><br />All together, 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.

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