Researchers at Emory University have uncovered the genetic and epigenetic mechanisms that drive the disease’s most lethal form. The study, published in Nature Genetics, maps how some prostate tumors evolve into an aggressive subtype known as neuroendocrine prostate cancer (NEPC), a transformation that occurs in approximately 20 percent of advanced cases and is strongly associated with poor outcomes.

The research team used cutting-edge single-cell technologies to trace how the architecture of DNA shifts over time in tumor cells. What they found was a progressive rewiring of chromatin, the structural material that packages DNA, leading to sweeping changes in gene expression. This reprogramming, the researchers discovered, is orchestrated by a pair of proteins: FOXA2 and NKX2-1. Acting as master regulators, FOXA2 unlocks specific chromatin regions, allowing NKX2-1 to activate genes that steer the cells toward a neuroendocrine identity.

The implications are significant. Unlike traditional prostate cancer, which typically relies on androgen receptor signaling and responds initially to hormone therapies, NEPC is treatment-resistant, fast-spreading, and often fatal. Understanding how this transformation happens at a molecular level opens the door to new ways of stopping it before it occurs. The Emory team tested one such approach by targeting the epigenetic regulators CBP and p300—proteins that help control gene activation. Using a drug currently in early-phase clinical trials, known as CCS1477, the scientists successfully blocked the neuroendocrine shift in lab and animal models.

While CCS1477 and other epigenetic drugs are still in experimental phases, the hope is that they could one day be used not only to treat NEPC but also to prevent its emergence in high-risk patients. The study also raises the possibility of new biomarkers that could identify early signs of neuroendocrine transformation, long before it becomes clinically apparent.

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