Researchers at Columbia University Irving Medical Center have identified a gene that drives the development of neuroendocrine prostate cancer (NEPC), an aggressive form of the disease. The study, to be published May 28 in the Journal of Experimental Medicine (JEM), shows that genetic or pharmacological inhibition of Sirtuin 1 prevents the growth of NEPC tumors in mice, and lays the groundwork for future clinical studies aimed at developing new treatments for NEPC in humans.
One in every six men will be affected by prostate cancer in their lifetime. The current standard of care is androgen deprivation therapy (ADT). However, it is well documented that ADT will eventually fail, leading to tumor recurrence and development of the ADT-insensitive aggressive prostate cancer variant, NEPC. The process through which ADT-responsive tumors transition towards NEPC tumors—a phenomenon known as lineage plasticity—remains unknown.
"Elucidating the mechanisms governing this process may improve treatment by overcoming plasticity-associated drug resistance," says Cory Abate-Shen, a professor at Columbia University Vagelos College of Physicians and Surgeons, who co-led the new JEM study with fellow professor Andrea Califano.
Abate-Shen's team performed a genetic screen in mice looking for mutations that recurred across multiple independent prostate cancer tumors. They identified 75 candidate NEPC-promoting genes, the most promising of which was Sirtuin 1 (Sirt1). Sirt1 encodes an enzyme with a broad range of functions, including control of gene expression and metabolism.
The group first looked to a human prostate cancer cell line to characterize the role of Sirt1. In these cells, the induction of NEPC produced an increase in the expression of genes predicted to be activated by SIRT1 and a corresponding decrease in those predicted to be downregulated by this protein. Confirming these results, the group found that activation of Sirt1 in cells with low SIRT1 expression levels led to a robust increase in key NEPC markers.
Recapitulating their cell line data, the team found that silencing of Sirt1 profoundly reduced tumor growth in mice with NEPC, indicating that Sirt1 is indeed a promising target for NEPC treatment. They also treated the tumors with the FDA-approved SIRT1-inhibitor, Selisistat, which was originally developed for treatment of Huntington's disease. Excitingly, the researchers saw that Selisistat administration significantly reversed the NEPC phenotype.
"Our findings demonstrate that SIRT1 plays a pivotal role in promoting NEPC, revealing a context-dependent function that extends beyond general tumor growth to the regulation of lineage plasticity and neuroendocrine differentiation," says Abate-Shen, adding that "this highlights SIRT1 as an attractive and clinically actionable target for lethal prostate cancer that warrants further investigation in future clinical studies."
Nunes de Almeida et al. 2026. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20241484?PR
