A forward genetic screen in mice identified 75 candidate genes linked to progression into the neuroendocrine prostate cancer (NEPC) state, with SIRT1 rising as the top hit. Activating SIRT1 increased NEPC markers in human cell models, while reducing or blocking SIRT1 sharply slowed tumor growth in mice. NEPC emerges after androgen-deprivation therapy as tumors bypass hormone blockade and return as treatment-insensitive subtypes. About one in eight men receive a prostate cancer diagnosis over their lifetimes, and lineage plasticity contributes to NEPC lethality. In mouse NEPC models, treatment with the selective SIRT1 inhibitor selisistat (EX-527) reversed neuroendocrine features and slowed tumor growth.
#neuroendocrine-prostate-cancer #sirt1 #androgen-deprivation-therapy #cancer-genetics #drug-repurposing
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