In a significant advancement for prostate cancer research, a first-of-its kind study led by Emory researchers uncovered how the disease transforms into its most lethal form—and identified a promising new treatment strategy.
The findings, published in Nature Genetics, offer critical insights into why some prostate cancers become resistant to therapy and how that shift could be blocked.
Researchers from Emory University have mapped a novel step-by-step process by which prostate cancer cells change into a more aggressive type known as neuroendocrine prostate cancer (NEPC). This transformation, which occurs in up to 20% of advanced cases, leads to rapid disease progression and currently has no effective treatment options.
"Prostate cancer is one of the most commonly diagnosed cancers, affecting countless patients and families," says lead author Jindan Yu, MD, PhD, a professor of urology in the Emory School of Medicine. "While it often responds well to hormone therapy, many cases eventually develop resistance. One major pathway leading to treatment failure and disease progression is the transformation of prostate tumor cells into NEPC, a new beast that lacks the targets for existing prostate cancer drugs."
Mapping the cells in 3D
Using cutting-edge genomic tools and in collaboration with Dr. Jonathan Zhao, associate professor in human genetics, the team created the first-ever 3D map of how prostate cancer cells rewire themselves over time to become a new threat. This map shows how the DNA folds and loops inside the cell nucleus—changes that help activate genes driving the deadly transformation.
The researchers discovered that two proteins—FOXA2 and NKX2-1—play a central role in this process. FOXA2 acts as a pioneer, opening up regions of DNA that are normally inaccessible. This allows NKX2-1, a gene typically found in brain and lung cells, to activate a new set of instructions that reprogram the cancer cells into NEPC. Yu explains that together, they reshape the cell's identity and drive its transition to a deadlier form.
The study also revealed that enzymes called CBP and p300 are essential for this deadly transformation as they evolve to turn on a new set of oncogenes (targets). Importantly, the researchers showed that CBP/p300-inhibiting drugs, such as CCS1477, currently in clinical trials, are able to target the moving targets and stop NEPC tumor growth in lab and animal models.
Why This Matters
This research has major implications for patients, families, and the future of prostate cancer treatment. By identifying the molecular drivers of NEPC and showing how to block them, the study opens the door to new therapies that could dramatically improve outcomes.
