Prostate Cancer Aggression: New Discovery
- University of Michigan Rogel Cancer Center researchers have identified a gene, PROX1, that plays a critical role in the development of aggressive, treatment-resistant prostate cancer.
- The research builds upon previous findings that prostate cancer cells can undergo lineage plasticity, a process where they become resistant to therapies targeting the androgen receptor.
- The team, led by Zhi Duan, Ph.D., discovered that PROX1 expression increases as prostate cancer cells transition to these alternate identities. Analysis of patient tumor biopsies revealed PROX1...
Researchers have pinpointed the PROX1 gene as a key driver of aggressive, treatment-resistant prostate cancer. this notable discovery indicates that existing drugs, such as HDAC inhibitors, may indirectly target PROX1, offering a new therapeutic approach. This research highlights how tumors evolve from a reliance on the androgen receptor. The team found that PROX1 expression correlates with lineage plasticity.Targeting PROX1 could effectively control these aggressive tumors. Find out more at News Directory 3, and discover how this breakthrough could revolutionize treatment.
PROX1 Gene Identified as Key Target in Aggressive Prostate Cancer
University of Michigan Rogel Cancer Center researchers have identified a gene, PROX1, that plays a critical role in the development of aggressive, treatment-resistant prostate cancer. The study, published in the Journal of Clinical Inquiry, suggests that existing drugs could indirectly target this gene, offering a new therapeutic avenue for patients with these tough-to-treat subtypes of prostate cancer.
The research builds upon previous findings that prostate cancer cells can undergo lineage plasticity, a process where they become resistant to therapies targeting the androgen receptor. This transition involves cancer cells adopting alternate identities, moving away from the typical reliance on the androgen receptor found in most prostate cancers.
The team, led by Zhi Duan, Ph.D., discovered that PROX1 expression increases as prostate cancer cells transition to these alternate identities. Analysis of patient tumor biopsies revealed PROX1 as a key upregulated gene in tumors exhibiting lineage plasticity.further investigation confirmed PROX1 as an early marker, especially in double-negative and neuroendocrine prostate cancers, which have low or no androgen receptor activity.
Experiments showed an inverse correlation between PROX1 and androgen receptor expression.Introducing PROX1 into prostate cancer cells led to the suppression of the androgen receptor. Eliminating PROX1 expression in double-negative and neuroendocrine prostate cancer cells halted their growth and induced cell death, indicating that targeting PROX1 could effectively control these tumors.
While directly targeting PROX1, a transcription factor, is challenging, the researchers explored PROX1’s protein partners. They found that PROX1 binds to histone deacetylases (HDACs), already known to play a role in cancer. This led to the hypothesis that HDAC inhibitors, some of which are FDA-approved for other cancers, might indirectly target PROX1.
The team discovered that PROX1-expressing prostate cancer cells were highly sensitive to HDAC inhibitors. treatment with these drugs depleted PROX1 protein, leading to tumor cell death, similar to the effects of genetically removing PROX1.
“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 Dr. Joshi J. Alumkal,senior study author and Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center.
“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,” Alumkal said.
“We examined the proteins that bind to PROX1.Among the top partners were histone deacetylases, or 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,” Alumkal said.
“Our work implicates PROX1 as an critically 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,” Alumkal said.
What’s next
The researchers suggest that clinical trials should prioritize HDAC inhibitors for patients with aggressive prostate cancer subtypes, offering a potential new treatment option for these challenging cases. Further research will explore the precise mechanisms by which PROX1 regulates the androgen receptor and how HDAC inhibitors can be optimized for targeting PROX1-expressing tumors.