Geneesmiddelenontwikkeling van middelgrote moleculen voor hoofd-halstumoren

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) arises from the squamous epithelium of the head and neck region, comprising heterogeneous lesions with distinct risk factors and diverse genetic and epigenetic alteration patterns. HNSCC is often difficult to control when lymph node metastasis has occurred, and treatment outcomes remain unsatisfactory. Elucidating the genetic and epigenetic profiles of cancer-associated genes is essential for improving clinical outcomes, yet to date the key molecules driving HNSCC progression remain unclear. HIGHLIGHT: We identified dickkopf Wnt signaling pathway inhibitor 3 (DKK3) as a candidate HNSCC-specific molecule that predicts prognosis. Our findings demonstrate that DKK3 expression is significantly elevated in cancer tissues relative to normal tissues and is associated with poor prognosis. Functional analyses have revealed that DKK3 exerts oncogenic effects by activating Akt signaling, driving increased cellular proliferation, migration, and invasion. We validated DKK3 as a potential therapeutic target, and developed complementary peptides to suppress its oncogenic activity. These DKK3 complementary peptides significantly inhibit HNSCC cell proliferation, invasion, and migration at low doses without detectable side effects and, in certain aspects, displayed superior performance over conventional HNSCC treatments including cisplatin and cetuximab. CONCLUSIONS: Peptide-based drug discovery, also referred to as medium-molecular-weight drug discovery, has attracted increasing attention, although few agents have reached clinical application. Our DKK3 complementary peptides are promising novel candidate therapeutics for HNSCC, raising expectations for future translational and clinical developments.