Researchers at the University of Michigan Rogel Cancer Center have identified a critical genetic mechanism that propels prostate cancer cells toward a more lethal, treatment-resistant state. The discovery, published in the Journal of Clinical Investigation, centers on the gene PROX1, which appears to play a pivotal role in "lineage plasticity"—a biological process that allows cancer cells to shed their original identity and evade conventional therapies. By identifying this gene, the research team has opened a potential pathway for treating some of the most aggressive and difficult-to-manage subtypes of prostate cancer using an existing class of drugs.
Prostate cancer is frequently driven by the androgen receptor, a protein that fuels the growth of most glandular prostate tumors. Consequently, standard treatments often focus on inhibiting this receptor to starve the cancer cells of the signals they need to proliferate. However, many patients eventually develop resistance to these therapies. When this happens, the cancer cells often undergo lineage plasticity, a complex transition where they abandon their reliance on the androgen receptor and adopt entirely new, often more aggressive, cellular identities.
"Patients whose prostate tumors lose reliance on the androgen receptor do poorly," explains senior study author Joshi J. Alumkal, M.D., the Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center. "Our results suggest a therapeutic approach for patients whose tumors have undergone that shift."
This transition represents a significant hurdle in modern oncology. As cancer cells shift away from their typical, androgen-dependent glandular state, they exist on a continuum of altered identities. Understanding the molecular drivers of this shift has long been a primary objective for researchers seeking to prevent or reverse the emergence of drug-resistant disease.
In this latest study, led by Zhi Duan, Ph.D., the University of Michigan team set out to pinpoint the specific factors that trigger this dangerous transition. Through an exhaustive examination of patient tumor biopsies, the researchers discovered that PROX1—a gene known for its role in regulating cell identity in both healthy and diseased tissue—becomes significantly more active as prostate cancer cells begin their transition to an alternate identity.
The team’s evidence for PROX1’s involvement was robust. When comparing hundreds of patient tumor samples across the spectrum of lineage plasticity, they found that PROX1 consistently appeared as a top upregulated gene. It served as a clear, early marker for the onset of this transformation. Specifically, the researchers observed that tumors with low androgen receptor activity, known as "double-negative prostate cancer," as well as tumors that had entirely lost expression of the androgen receptor, known as "neuroendocrine prostate cancer," consistently activated the PROX1 gene.
Further experiments reinforced the inverse relationship between the two. When the researchers added PROX1 to prostate cancer cells in a laboratory setting, the androgen receptor was effectively turned off. This strongly suggests that PROX1 acts as a regulator, potentially suppressing the androgen receptor and driving the tumor to discard its glandular identity in favor of a more aggressive, resistant form. "We think PROX1 is regulating the androgen receptor," Alumkal noted. "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."
Having established the role of PROX1 as an early driver of this shift, the research team then tested whether removing the gene could halt the progression of the disease. Using genetic methods, they eliminated PROX1 expression in both double-negative and neuroendocrine prostate cancer cell models. The results were striking: the cells stopped growing and, in many cases, began to die. This indicated that PROX1 is not merely a marker of the disease, but a functional engine that the cancer relies upon for survival once it has transitioned.
However, translating this finding into a clinical treatment presented a significant hurdle. PROX1 is a transcription factor, a type of protein that functions by binding to DNA to activate genes. Transcription factors have historically been notoriously difficult to target with small-molecule drugs because of their complex shapes and lack of traditional "pockets" where drugs can bind. Faced with this challenge, the team adopted a strategy often described as "guilt by association."
The researchers investigated the proteins that interact with PROX1, looking for partners that might be easier to target. Among the most prominent binding partners were histone deacetylases, commonly referred to as HDACs. HDACs are enzymes that modify the structure of chromatin, influencing which genes are turned on or off. Because HDACs work in close cooperation with transcription factors like PROX1 to facilitate cellular changes, the team hypothesized that inhibiting HDACs might effectively disrupt the function of the PROX1 complex, even if they could not target the PROX1 protein directly.
This hypothesis proved successful. The team found that prostate cancer cells expressing high levels of PROX1 were exceptionally sensitive to HDAC inhibitors. When treated with these drugs, the PROX1 protein was depleted, and the cancer cells began to die, mirroring the results seen when the researchers genetically removed the gene.
This finding is particularly encouraging because HDAC inhibitors are not entirely new to medicine. Several drugs in this class have already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other types of cancer. This existing track record could potentially expedite the process of moving these therapies into clinical trials for patients with aggressive, treatment-resistant prostate cancer.
"Our work implicates PROX1 as an important early driver away from androgen receptor dependence," Alumkal said. "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."
The study, which involved a vast collaboration of researchers and was supported by an extensive network of funding organizations, including the National Institutes of Health, the U.S. Department of Defense, and the Prostate Cancer Foundation, represents a major step forward in precision oncology. By identifying the specific molecular "switch" that allows prostate cancer to become treatment-resistant, the team has provided a clear rationale for shifting the focus toward therapies that can disrupt this plasticity.
As the scientific community continues to explore the mechanisms of lineage plasticity, the discovery of the PROX1-HDAC axis offers a rare opportunity to repurpose existing pharmacological tools to combat some of the most challenging forms of cancer. While clinical trials will be necessary to confirm the efficacy and safety of using HDAC inhibitors in this specific patient population, the findings offer a renewed sense of hope for patients who have exhausted standard hormone-based treatments and are in urgent need of new therapeutic strategies.
