Landscape of Prostate-Specific Membrane Antigen Heterogeneity and Regulation in AR-Positive and AR-Negative Metastatic Prostate Cancer

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15–20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. 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. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers.

Martin K. Bakht, Yasutaka Yamada, Sheng-Yu Ku, Varadha Balaji Venkadakrishnan, Joshua A. Korsen, Teja M. Kalidindi, Kei Mizuno, Shin Hye Ahn, Ji-Heui Seo, Maria Mica Garcia, Francesca Khani, Olivier Elemento, Henry W. Long, Alain Chaglassian, Nagavarakishore Pillarsetty, Jason S. Lewis, Matthew Freedman, Anthony P. Belanger, Quang-De Nguyen & Himisha Beltran

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Molecular Cancer Imaging Facility, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; Blue Earth Diagnostics, Burlington, MA, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA, USA.

Source: Bakht, M.K., Yamada, Y., Ku, SY. et al. Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer. Nat Cancer (2023). https://doi.org/10.1038/s43018-023-00539-6.

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Exploring the Complexities of PSMA Heterogeneity and Regulation in Metastatic Prostate Cancer with AR-Positive and AR-Negative Phenotypes - Misha Beltran

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