Therapeutics: β-catenin (CTNNB1); ubiquitin specific peptidase 6 (USP6)
Cell culture and mouse studies suggest inhibiting Wnt/CTNNB1 signaling could help treat nodular fasciitis, alveolar rhabdomyosarcoma and other USP6-overexpressing cancers. Screening of siRNA libraries in HEK cells and a human sarcoma cell line identified USP6 as an activator of Wnt/CTNNB1 pathway signaling. In a xenograft mouse model of nodular fasciitis, tumor expression of dickkopf homolog 1 (DKK1), a negative regulator of Wnt/CTNNB1 signaling, decreased tumor growth compared with unmodified DKK1 expression. In a xenograft mouse model of USP6-overexpressing alveolar rhabdomyosarcoma, a tool compound that inhibits porcupine homolog (PORCN), a component of the Wnt/CTNNB1 pathway, decreased tumor growth compared with vehicle. Next steps could include testing Wnt/CTNNB1 pathway inhibitors in models of other USP6-overexpressing cancers.
Novartis AG has LGK974, an oral PORCN inhibitor, in Phase I/II testing to treat breast cancer and metastatic melanoma and Phase I testing to treat cancer dependent on Wnt ligands...