University of Michigan study reveals PROX1’s role in treatment-resistant prostate cancer and proposes repurposing existing drugs
Scientists at the University of Michigan Rogel Cancer Center have discovered that the PROX1 gene plays a critical role in prostate cancer’s transition to a more aggressive, treatment-resistant form. Their findings, published in the Journal of Clinical Investigation, suggest that existing HDAC inhibitor drugs could potentially target this pathway.
Breaking Androgen Receptor Dependence
The research builds upon previous work showing that prostate cancer cells can undergo lineage plasticity – a process where they become resistant to therapies targeting the androgen receptor, which is crucial in most prostate cancers. This transition represents a continuum where cancer cells adopt alternate identities.
“Patients whose prostate tumors lose reliance on the androgen receptor have poor outcomes. Our results suggest a therapeutic approach for these cases,” said senior author Dr. Joshi J. Alumkal, the Wicha Family Professor of Oncology at Michigan Medicine.
PROX1 Emerges as Key Player
Led by Dr. Zhi Duan, the team analyzed patient tumor biopsies that had undergone lineage plasticity, identifying PROX1 as the most upregulated gene. Their examination of hundreds of tumors confirmed PROX1 as an early marker of this transition.
The study revealed that PROX1 expression increases as prostate cancer cells shift away from androgen receptor dependence. Tumors with low androgen receptor activity (double-negative prostate cancer) and those completely lacking receptor expression (neuroendocrine prostate cancer) consistently activated PROX1.
“We believe PROX1 regulates the androgen receptor, potentially explaining why it gets turned off during lineage plasticity,” Dr. Alumkal explained.
Potential Therapeutic Pathway
When researchers genetically removed PROX1 from aggressive prostate cancer cells, the cells stopped growing and began dying. However, directly targeting transcription factors like PROX1 with drugs remains challenging.
The team discovered that PROX1 interacts with histone deacetylases (HDACs), proteins already implicated in cancer. Several HDAC inhibitors are FDA-approved for other cancers.
Experiments showed PROX1-expressing cells were highly sensitive to HDAC inhibitors, which reduced PROX1 protein levels and caused tumor cell death – mirroring the effects of genetic PROX1 removal.
Clinical Implications
“Our work positions PROX1 as an early driver away from androgen receptor dependence,” Dr. Alumkal stated. “HDAC inhibitors block PROX1 and reduce survival in aggressive prostate cancer models. This class of drugs should be prioritized for clinical trials in aggressive prostate cancer subtypes with limited treatment options.”
The study involved collaboration with numerous researchers and was supported by multiple grants from the National Institutes of Health, Department of Defense, Prostate Cancer Foundation, and other organizations.
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