Gene Identified as Potentially Driving More Aggressive Prostate Cancer

Researchers at the University of Michigan Health Rogel Cancer Center have identified a gene that may lead to a more aggressive, treatment-resistant form of prostate cancer. The gene can be indirectly targeted with an existing class of drugs, suggesting a potential treatment strategy for patients with aggressive subtypes of prostate cancer.¹

The work advances earlier studies that linked prostate cancer cells that underwent lineage plasticity, in which they become resistant to targeting the androgen receptor, a key target in prostate cancer. This transition away from dependence on the androgen receptor is a continuum with cancer cells taking on alternate identities from what is typical in most prostate cancers that rely on the androgen receptor.

In this study, Zhi Duan, PhD, and colleagues identified the gene PROX1, which plays a role in dictating cell identity in both normal cells and cancer cells. The team noted that as prostate cancer cells transition to an alternate identity, PROX1 becomes more highly expressed.

By examining hundreds of patient tumors along the continuum of lineage plasticity, they confirmed PROX1 as an early marker of lineage plasticity. Indeed, they found that double-negative prostate cancer tumors, in addition to neuroendocrine prostate cancer tumors, turn on PROX1.

In additional experiments, the team noted that PROX1 expression was inversely correlated with androgen receptor expression in prostate cancer patient tumor datasets. Adding PROX1 to prostate cancer cells also turned off the androgen receptor.

“Patients whose prostate tumors lose reliance on the androgen receptor do poorly. Our results suggest a therapeutic approach for patients whose tumors have undergone that shift,” senior study author Joshi J. Alumkal, MD, Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center, explained in a press release about the results.² “We think PROX1 is regulating the androgen receptor. It may be one explanation for why the androgen receptor gets turned off when tumors undergo lineage plasticity and transition away from the typical glandular prostate cancer identity.”

Next, the team eliminated PROX1 expression with genetic methods in both double-negative prostate cancer and neuroendocrine prostate cancer cells.

The cells then stopped growing and began to die, suggesting that targeting PROX1 could be an effective way to control these tumors.

One challenge is that PROX1 is a transcription factor, meaning its function to turn on genes, and this type of protein is notoriously difficult to target with drugs. Looking for a workaround, the team turned to the company PROX1 keeps.

“We examined the proteins that bind to PROX1. Among the top partners were histone deacetylases (HDACs). We felt like this was guilt by association. We hypothesized that HDACs might cooperate with PROX1 and that targeting HDACs might be like targeting PROX1,” Dr Alumkal noted.

HDACs are already known to play a role in cancer, and several HDAC inhibitors have been approved by the FDA for cancers other than prostate.

The team concluded that PROX1-expressing prostate cancer cells were very sensitive to HDAC inhibitors, and treatment with these drugs depleted PROX1 protein. As PROX1 expression decreased, the tumor cells died. The impact was similar to when the team genetically removed PROX1 from the cells.

“Our work implicates PROX1 as an important early driver away from androgen receptor dependence. HDAC inhibitors can block PROX1 and reduce survival of aggressive prostate tumor models that have transitioned away from androgen receptor reliance. Our results suggest this class of drugs should be prioritized for clinical trials in patients who have aggressive prostate cancer subtypes, for which there are few treatment options,” Dr Alumkal concluded.

References

1. Duan Z, Shi M, Kumaraswamy A, et al. PROX1 is an early driver of lineage plasticity in prostate cancer. J Clin Invest. 2025;135:e187490.
2. Fawcett N. Researchers find early driver of prostate cancer aggressiveness [press release]. June 2, 2025. Accessed August 15, 2025. www.michiganmedicine.org/health-lab/researchers-find-early-driver-prostate-cancer-aggressiveness