Columbia University scientists say they have homed in on a gene that appears to drive one of the deadliest forms of prostate cancer, and shutting it down in mice made stubborn tumors shrink. The work focuses on Sirtuin 1 (SIRT1), an enzyme that regulates gene activity and metabolism and that the team links to treatment-resistant neuroendocrine prostate cancer (NEPC).
Genetic screen points to SIRT1
Using a forward genetic screen in mice, the Columbia group looked for mutations that kept popping up across independent tumors and landed on 75 candidate genes that might help push prostate cancer into the NEPC state. SIRT1 quickly rose to the top of the list: turning the gene on boosted NEPC markers in human cell models, while dialing it down or blocking it with a drug sharply slowed tumor growth in mice, according to a study in the Journal of Experimental Medicine.
Why this matters for treatment resistance
Standard first-line care for prostate cancer is androgen-deprivation therapy, which cuts off the hormones many tumors rely on. Over time, though, a subset of cancers finds a way around that blockade and comes back as treatment-insensitive subtypes such as NEPC.
About one in eight men will hear a prostate cancer diagnosis at some point in their lives, according to the National Cancer Institute. Some populations face even steeper odds. The cellular shape-shifting, or lineage plasticity, that leads to NEPC is one of the reasons advanced disease can turn lethal. “SIRT1 plays a pivotal role in promoting NEPC,” co-author Cory Abate-Shen said in a news release via EurekAlert!.
Mouse tests and a repurposed drug
Once SIRT1 emerged as a suspect, the team moved to the obvious next question: can it be safely targeted. In mouse models of NEPC, the researchers treated tumors with the selective SIRT1 inhibitor selisistat (also known as EX-527) and report that the drug reversed neuroendocrine features and slowed tumor growth, per the Journal of Experimental Medicine.
Selisistat, also labeled EX-527 or SEN0014196, was originally developed for Huntington's disease and has already been through early human testing, although it is not an approved treatment. An exploratory human study, described in the medical literature, suggests the drug was generally well tolerated in that setting, but larger, cancer-focused trials would be required to say anything meaningful about how well it works or how safe it is for people with prostate cancer (clinical trial report).
Next steps and cautions
The authors argue that their data “highlight SIRT1 as an attractive and clinically actionable target,” but they and outside experts are quick to note that success in mice does not automatically translate to people. Carefully designed early-phase trials will be needed to test whether SIRT1 inhibition can actually help patients with advanced disease. The study, published May 28, has already picked up attention from local media, including coverage in The Mercury.
The work was led by teams at Columbia University Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center, with senior authors Cory Abate-Shen and Andrea Califano. More on their ongoing prostate cancer research is available on Columbia's Abate-Shen Lab.
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