Researchers at Columbia University Irving Medical Center have pinpointed the gene responsible for one of prostate cancer's most lethal transformations. The discovery centers on Sirtuin 1 (Sirt1), a key driver of neuroendocrine prostate cancer (NEPC), an aggressive form of the disease that emerges when standard treatments fail. The findings, published in the Journal of Experimental Medicine, offer a concrete pathway toward new treatments for a cancer that has long resisted conventional approaches.
One in every six men will face prostate cancer in his lifetime. For most, androgen deprivation therapy (ADT)—the current standard of care—works initially. But it nearly always fails eventually, triggering a dangerous shift. Tumors evolve into NEPC, a drug-resistant variant far more aggressive than the original disease. This transformation, called lineage plasticity, has mystified researchers for years. Understanding what drives it could unlock treatments that overcome the resistance that makes NEPC so deadly.
Cory Abate-Shen, a professor at Columbia University Vagelos College of Physicians and Surgeons, led the research with fellow professor Andrea Califano. Their team conducted a genetic screen in mice, hunting for mutations that appeared repeatedly across independent prostate cancer tumors. They identified 75 candidate genes that promote NEPC. Among them, Sirt1 stood out—an enzyme that regulates gene expression and metabolism across multiple biological systems.
The evidence mounted quickly. In human prostate cancer cells, when NEPC developed, genes activated by SIRT1 surged while those it suppresses declined. Activating SIRT1 in cells with naturally low levels triggered a robust increase in key NEPC markers. The team then tested whether silencing the gene in mice would slow tumor growth. It did—profoundly. Tumors in mice without functional Sirt1 were significantly smaller than those in mice with normal Sirt1 expression.
What made the discovery particularly promising was the team's next move. They treated tumors with Selisistat, an FDA-approved drug originally developed for Huntington's disease that inhibits SIRT1. The results were striking: Selisistat significantly reversed the NEPC phenotype, shrinking the aggressive tumors in mouse models.
This matters because it means researchers aren't starting from scratch. A drug that works on SIRT1 already exists and has been tested in humans. The pathway from mouse studies to clinical trials—normally the longest and most uncertain step in cancer research—suddenly looks clearer. Abate-Shen describes SIRT1 as "an attractive and clinically actionable target for lethal prostate cancer that warrants further investigation in future clinical studies."
The study does more than identify a single gene. It reveals how prostate cancer hijacks a fundamental cellular mechanism to transform itself. By blocking that mechanism, researchers may finally interrupt the progression that makes NEPC so difficult to treat. For the millions of men diagnosed with prostate cancer each year, and especially those whose tumors begin to resist standard therapy, this discovery represents a genuinely new direction—one rooted not in hope alone, but in biology that researchers can already manipulate with existing tools.