Prostate-specific membrane antigen (PSMA) is a biomarker that can tell physicians much about a patient’s metastatic prostate cancer. However, in 15–20% of patients with castration-resistant prostate cancer, PSMA production stops at advanced stages of the disease. Now, researchers at Dana-Farber Cancer Institute have identified a mechanism that raises and lowers PSMA expression in prostate cancer cells. The findings may help physicians select PSMA-targeting therapies for specific patients, researchers say.
The findings are published in Nature Cancer in a paper titled, “Landscape of Prostate-Specific Membrane Antigen Heterogeneity and Regulation in AR-positive and AR-negative Metastatic Prostate Cancer.”
“Tumor expression of PSMA is lost in 15–20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined,” wrote the researchers. “In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with 18F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer.”
The study led by Dana-Farber’s Himisha Beltran, MD, and Martin Bakht, PhD, found that PSMA expression is lower in liver metastases than in other parts of the body, regardless of expression of the AR.
The researchers also observed that some tumors that test negative for the AR do express PSMA and that some AR-positive tumors don’t.
The study authors also identified amino acids that are upregulated in metastatic prostate tumors low in PSMA.
The discovery may lead to new biomarkers that complement PSMA imaging in identifying prostate cancer subtypes.