In a significant advancement for the field of oncology, researchers at the University of Michigan Rogel Cancer Center have identified a specific gene that serves as a primary driver in the development of aggressive, treatment-resistant prostate cancer. The discovery not only sheds light on the biological mechanisms that allow cancer cells to evade standard therapies but also points toward a potential treatment strategy using an existing class of drugs. By targeting the protein products of this gene indirectly, clinicians may soon have a new way to combat the most lethal forms of the disease.
Prostate cancer remains one of the most common malignancies among men, and while many cases are slow-growing and highly treatable, a subset of patients develops aggressive forms that stop responding to conventional medicine. For decades, the cornerstone of treatment for advanced prostate cancer has been androgen deprivation therapy. This approach works by blocking the androgen receptor, a protein that prostate cancer cells typically rely on to grow and survive. However, the cancer often finds a way to adapt.
"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," said the study’s senior author, Joshi J. Alumkal, M.D., the Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center.
The study, which was recently published in the Journal of Clinical Investigation, focuses on a phenomenon known as lineage plasticity. This is a process by which cancer cells essentially "shapeshift," moving away from their original identity as glandular prostate cells—which are dependent on the androgen receptor—and taking on new identities that allow them to thrive even when the androgen receptor is inhibited. This transition is not an overnight event but rather a continuum, where cells gradually lose their original characteristics and adopt alternate survival mechanisms.
Led by Zhi Duan, Ph.D., the research team sought to uncover the specific factors that trigger this dangerous transition. Through an exhaustive analysis of patient tumor biopsies, the researchers identified a gene called PROX1 as a major culprit. PROX1 is a transcription factor, a type of protein responsible for dictating cell identity in both healthy development and the progression of disease. The team observed that as prostate cancer cells began to move away from their dependence on the androgen receptor, the expression of PROX1 increased significantly.
The investigation into PROX1 began with a close look at the molecular landscape of tumors that had already undergone lineage plasticity. When comparing these aggressive samples to more typical prostate cancers, PROX1 emerged as the most highly upregulated gene. To confirm these findings, the researchers examined hundreds of patient tumors across the entire spectrum of lineage plasticity. They discovered that PROX1 serves as an early marker of this shift, appearing even before the cancer has fully transformed into its most resistant state.
Specifically, the study found that PROX1 is turned on in "double-negative" prostate cancer—tumors that have low androgen receptor activity—as well as in neuroendocrine prostate cancer, an extremely aggressive subtype where the expression of the androgen receptor is lost entirely. In additional experiments, the team demonstrated a clear inverse relationship: when PROX1 levels are high, androgen receptor levels are low. In fact, when the researchers artificially introduced PROX1 into prostate cancer cells in the lab, it effectively turned off the androgen receptor, mimicking the transition seen in the most difficult-to-treat patients.
"We think PROX1 is regulating the androgen receptor," Alumkal explained. "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."
This realization provided a clear target for intervention, but targeting PROX1 directly presented a major hurdle. As a transcription factor, PROX1 lacks the type of "binding pockets" that traditional small-molecule drugs use to latch onto a protein. Transcription factors are notoriously difficult to target with drugs, often described by scientists as "undruggable." To overcome this, the Michigan team decided to look at the molecular "company" that PROX1 keeps—the other proteins it interacts with to carry out its function.
By mapping the proteins that bind to PROX1, the researchers found that it frequently partners with histone deacetylases, commonly known as HDACs. This discovery provided a breakthrough moment for the team. "We felt like this was guilt by association," Alumkal said. "We hypothesized that HDACs might cooperate with PROX1 and that targeting HDACs might be like targeting PROX1."
This was a particularly promising lead because HDACs are already well-known in the world of cancer research. Several HDAC inhibitors have already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other types of cancer, such as certain lymphomas and multiple myeloma. While they had not yet found a primary role in the treatment of prostate cancer, the connection to PROX1 suggested they might be the "missing link" needed to treat aggressive subtypes.
The team tested this hypothesis by treating PROX1-expressing prostate cancer cells with HDAC inhibitors. The results were striking. The drugs not only inhibited the activity of the cells but actually led to the depletion of the PROX1 protein itself. As the levels of PROX1 dropped, the cancer cells began to die. The effect of the drugs was nearly identical to the results the team achieved when they used sophisticated genetic methods to "knock out" or eliminate the PROX1 gene entirely.
This suggests that by using HDAC inhibitors, doctors might be able to effectively "turn off" the driver of lineage plasticity and stop the growth of tumors that have become resistant to standard hormone therapies. Because these drugs are already FDA-approved for other indications, the path to clinical trials for prostate cancer patients could be significantly shorter than it would be for an entirely new compound.
"Our work implicates PROX1 as an important early driver away from androgen receptor dependence," Alumkal noted. "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 implications of this research are far-reaching. For patients currently facing a diagnosis of double-negative or neuroendocrine prostate cancer, the prognosis has historically been poor due to the lack of targeted therapies. By identifying PROX1 as an early marker, doctors may one day be able to use diagnostic tests to identify patients whose tumors are just beginning to undergo lineage plasticity, allowing for earlier intervention with HDAC inhibitors before the cancer becomes fully resistant.
The study was a massive collaborative effort involving dozens of researchers from various institutions. Along with lead author Zhi Duan and senior author Joshi J. Alumkal, the contributing authors include Mingchen Shi, Anbarasu Kumaraswamy, Dong Lin, Dhruv Khokhani, Yong Wang, Chao Zhang, Fiana Flores, Eva Rodansky, Olivia A. Swaim, William K. Storck, Hannah Beck, Radhika A. Patel, Erolcan Sayar, Brian P. Hanratty, Hui Xue, Xin Dong, Zoe R. Maylin, Rensheng Wan, David A. Quigley, Martin Sjostrom, Ya-Mei Hu, Faming Zhao, Zheng Xia, Siyuan Cheng, Xiuping Yu, Felix Y. Feng, Li Zhang, Rahul Aggarwal, Eric J. Small, Visweswaran Ravikumar, Arvind Rao, Karan Bedi, John K. Lee, Colm Morrissey, Ilsa Coleman, Peter S. Nelson, Eva Corey, Aaron Udager, Ryan Rebernick, Marcin P. Cieslik, Arul M. Chinnaiyan, Joel A. Yates, Michael C. Haffner, and Yuzhuo Wang.
The breadth of the research was supported by a wide array of funding sources, underscoring the importance of the findings to the medical community. Significant support was provided by multiple grants from the National Institutes of Health (NIH), including CA251245, CA282005, CA186786, P30CA046592, T90DE030859, GM147365, CA214955-01A1, CA274336, P50CA97186, and CA163227. Additional funding came from the U.S. Department of Defense, the Joint Institute for Cancer Research, the Prostate Cancer Foundation, the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Canadian Cancer Society, the BC Cancer Foundation, the Smith Family Scholar Award, the Sheppard Family Foundation, the Benioff Initiative for Prostate Cancer Research, the Silver Family Innovation Foundation, the National Science Foundation, and the Institute for Prostate Cancer Research.
As the research moves toward the clinical trial phase, the focus will remain on identifying the specific patient populations most likely to benefit from HDAC inhibition. By targeting the "shapeshifting" ability of prostate cancer cells, the team at the University of Michigan Rogel Cancer Center is opening a new chapter in the fight against one of the most challenging forms of the disease.
