Posted: Wednesday, July 12, 2023
Himisha Beltran, MD, of Dana-Farber Cancer Institute, Boston, and colleagues aimed to investigate the heterogeneity and regulation of prostate-specific membrane antigen (PSMA) in metastatic prostate cancer, particularly in androgen receptor (AR)-positive and AR-negative castration-resistant prostate cancer. Their findings, which indicated that PSMA expression may be lower in liver metastases than in other parts of the body, regardless of expression of the AR, were published in Nature Cancer. The discovery may lead to new biomarkers that complement PSMA imaging in identifying prostate cancer subtypes.
The study found that PSMA expression is lost in 15% to 20% of men with castration-resistant prostate cancer, and the underlying mechanism responsible for this loss is not well understood. Through animal models, the investigators observed lower PSMA expression in liver lesions than in other sites of the body, including in AR-positive castration-resistant prostate cancer. This suggests that the microenvironment seems to play a role in modulating PSMA expression.
The suppression of PSMA was associated with specific molecular changes; for instance, histone 3 lysine 27 methylation in the PSMA promoter and increased levels of neutral amino acid transporters. These changes correlated with increased uptake of 18F-fluciclovine, as observed in PET imaging.
Although PSMA is known to be regulated by the AR, the investigators identified a subset of AR-negative castration-resistant prostate cancer cases with high PSMA expression. Through further investigation, they discovered that HOXB13, a gene associated with prostate development, and AR co-occupy the PSMA enhancer region. Knockout models supported the role of HOXB13 as an upstream regulator of PSMA in both AR-positive and AR-negative prostate cancer.
Understanding the factors influencing PSMA expression may help to determine the effectiveness of PSMA-targeted treatments and identify patients who are likely to benefit from these therapies. Additionally, the identification of HOXB13 as a regulator of PSMA in AR-negative prostate cancer opens new possibilities for targeting PSMA in patients who do not respond to conventional AR-targeted therapies.
Disclosure: For full disclosures of the study authors, visit nature.com/articles.