63 Quick summary: Groundbreaking oncology research from Columbia University Irving Medical Center has identified a specific gene known as Sirtuin 1 that drives the development of an aggressive, treatment resistant form of prostate cancer by regulating cell lineage plasticity. Laboratory trials demonstrate that silencing this gene or administering an existing drug originally developed for Huntington’s disease profoundly restricts tumour growth and reverses the malignant cancer phenotype. These clinical findings carry vital implications for healthcare practice and public policy, offering an accelerated precision medicine pathway to overcome therapeutic resistance and directly improve survival rates and long term well being for patients facing terminal diagnoses. Researchers at Columbia University Irving Medical Center have identified a gene that drives the development of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant form of the disease. The study, published on 28th May in the Journal of Experimental Medicine, shows that inhibiting Sirtuin 1 (SIRT1) prevents tumour growth in mice, laying the groundwork for future clinical trials. 1 in 6 men will develop Prostate Cancer during their lifetime. The current standard of care is androgen deprivation therapy (ADT), which eventually fails in many patients, leading to tumour recurrence and the development of NEPC. The process by which ADT-responsive tumours transform into NEPC tumours, known as lineage plasticity, has remained poorly understood. “Elucidating the mechanisms governing this process may improve treatment by overcoming plasticity-associated drug resistance,” said Cory Abate-Shen, a professor at Columbia University Vagelos College of Physicians and Surgeons, who co-led the study with fellow professor Andrea Califano. Abate-Shen’s team conducted a genetic screen in mice, searching for mutations recurring across multiple independent prostate cancer tumours. They identified 75 candidate Neuroendocrine Prostate Cancer-promoting genes, with Sirtuin 1 emerging as the most promising candidate. SIRT1 encodes an enzyme involved in a broad range of functions, including the control of gene expression, and metabolism. In human prostate cancer cell lines, the induction of NEPC produced an increase in genes activated by SIRT1 and a corresponding decrease in those it suppresses. Activating SIRT1 in cells with low baseline expression led to a marked increase in key NEPC markers, confirming the gene’s role in driving the disease. Silencing Sirtuin 1 in mice with NEPC profoundly reduced tumour growth. The team also tested Selisistat, an FDA-approved SIRT1 inhibitor originally developed for Huntington’s Disease, and found that it significantly reversed the NEPC phenotype in treated tumours. “Our findings demonstrate that SIRT1 plays a pivotal role in promoting NEPC, revealing a context-dependent function that extends beyond general tumour growth to the regulation of lineage plasticity and neuroendocrine differentiation,” Abate-Shen said. “This highlights SIRT1 as an attractive and clinically actionable target for lethal prostate cancer that warrants further investigation in future clinical studies.” Neuroendocrine Prostate Cancer is known for its rapid progression and resistance to standard therapies, highlighting the urgent need for new approaches in patients with limited options after ADT failure. The team’s findings point toward a precision medicine strategy targeting epigenetic regulators, and metabolic pathways that cancer cells exploit during disease progression. Because Selisistat has already undergone human testing for another condition, its availability could accelerate the path toward clinical evaluation for Prostate Cancer. Further studies will be needed to translate these preclinical findings into human trials, but the results represent a meaningful step toward improving survival outcomes for patients with aggressive disease.