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Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer

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From Nature Reviews Urology

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Abstract

Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity — including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment — affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

Key points

  • Prostate-specific membrane antigen (PSMA) is an in-demand targetable transmembrane folate hydrolase enzyme used for PET imaging and targeted therapy using α- and β-emitters.

  • PSMA expression is often suppressed in androgen receptor-negative advanced prostate cancers and in liver metastases, presenting a challenge for patient management and a need for alternative theranostic targets for these patients.

  • The PSMA regulatory network comprises a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) promoter, intergenic enhancers and differentially methylated regions.

  • Regardless of PSMA expression levels in tumour tissue, a definition of PSMA positivity using PET is a prerequisite for the use of PSMA-radioligand therapy. Adjunctive companion imaging methods, such as fluorodeoxyglucose-PET or other tracers, might improve patient selection for PSMA-targeted therapies.

  • Our understanding of PSMA heterogeneity is expanding across cellular, tumoural and spatial, inter-patient, intra-patient, intra-lineage, inter-lineage and temporal dimensions.

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Fig. 1: PSMA enzymatic active site and its crosstalk with other signalling pathways in prostate cancer.
Fig. 2: PSMA expression in prostate luminal epithelium.
Fig. 3: GUL-based targeting of the PSMA enzymatic active site in prostate cancer.
Fig. 4: PSMA suppression during progression of prostate cancer.
Fig. 5: Defining PSMA positivity is essential for selecting patients for PSMA-RLT.
Fig. 6: The complexity of PSMA heterogeneity demands a more nuanced approach.
Fig. 7: Genomic and epigenomic features of the PSMA regulatory network.
Fig. 8: Cellular internalization of PSMA and exposure of DNA to radiation following uptake of PSMA-radioligand.

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Acknowledgements

This work supported by the Prostate Cancer Foundation, Department of Defense (W81XWH-17-1-0653 to H.B., W81XWH-22-1-0010 to M.K.B.), and NIH/NCI (R37CA241486 and P50CA272390 to H.B.).

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  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Martin K. Bakht & Himisha Beltran

  2. Harvard Medical School, Boston, MA, USA

    Martin K. Bakht & Himisha Beltran

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The authors contributed equally to all aspects of the article.

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Correspondence to Himisha Beltran.

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H.B. has served as consultant/advisory board member for Janssen, Astellas, AstraZeneca, Merck, Pfizer, Blue Earth Diagnostics, Amgen, Bayer, Daicchi Sankyo, Sanofi and Novartis, and has received research funding (to institution) from Janssen, AbbVie/Stemcentrx, Bristol Myers Squibb, Circle Pharma, Novartis and Daicchi Sankyo. M.K.B. declares no competing interests.

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Bakht, M.K., Beltran, H. Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00900-z

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