Publication Date:
2019
Description:
〈p〉The Wnt/β-catenin (β-cat) pathway plays a critical role in cancer. Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of β-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L). We identified a set of peptides, including hsBCL9〈sub〉CT〈/sub〉-24, that robustly inhibits the activity of β-cat and suppresses cancer cell growth. In animal models, these peptides exhibit potent anti-tumor effects, favorable pharmacokinetic profiles, and minimal toxicities. Markedly, these peptides promote intratumoral infiltration of cytotoxic T cells by reducing regulatory T cells (T〈sub〉reg〈/sub〉) and increasing dendritic cells (DCs), therefore sensitizing cancer cells to PD-1 inhibitors. Given the strong correlation between T〈sub〉reg〈/sub〉 infiltration and 〈i〉APC〈/i〉 mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway. In summary, we report a promising strategy for cancer therapy by pharmacological inhibition of the Wnt/β-cat signaling.〈/p〉
Electronic ISSN:
2375-2548
Topics:
Natural Sciences in General
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