Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer
Open accessAbstract
Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177 Lu-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.
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PSMA expression is strongly correlated with extent of disease but varies significantly among patients and even within tumor sites in the same patient.
“While PSMA expression is strongly correlated with extent of disease, this varies significantly among patients and even within tumor sites in the same patient.”
From PSMA-based Therapies and Novel Therapies in Advanced Prostate Cancer: The Now and the Future (2025) · cites this paper as [35]
The Fig. 5 caption describes inter-patient and intrapatient PSMA heterogeneity, and the ‘Manifestation of pathological PSMA heterogeneity’ section discusses PSMA-positive and PSMA-negative regions within a tumour. The passages do not establish a strong correlation between PSMA expression and extent of disease; the Conclusions instead note that some late-stage cancers lose PSMA expression. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPSMA expression heterogeneity can lead to variable response rates to PSMA-targeted therapies and leave a treatment gap in patients with non-PSMA expressing prostate cancer, furthering the need for alternate biomarker investigation.
“This heterogeneity can lead to variable response rates to PSMA-targeted therapies and leave a treatment gap in patients with non-PSMA expressing prostate cancer, furthering the need for alternate biomarker investigation”
From PSMA-based Therapies and Novel Therapies in Advanced Prostate Cancer: The Now and the Future (2025) · cites this paper as [35]
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References 160 · Cited by 158
Research works printed but not linked: 1
- [47]47. Uhlén M et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015). [PubMed: 25613900]
- Authors
- Bakht, M. K., & Beltran, H.
- Affiliations
- Harvard University (US)
- Corresponding author
- Beltran, Himisha
- Venue
- Nature Reviews Urology
- Published
- 2024-07-08
- Volume
- 22
- Issue
- 1
- Pages
- 26-45
- ISSN
- 1759-4812 (ISSN-L)
- 1759-4820
- PMC
- PMC11841200
- OpenAlex
- W4400414544
- Cited by
- 158
- References
- 160
- Citations by year
- 2026: 89 · 2025: 63 · 2024: 6
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Reviews Urology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (#W81XWH-17, W81XWH2210010, W81XWH1710653, W81XWH)
- Prostate Cancer Foundation (W81XWH-17-1-0653)
- National Institutes of Health (W81XWH)
- National Cancer Institute (R37CA241486, P50CA272390)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- prostate-specific membrane antigen, prostate cancer, castration-resistant prostate cancer, PSMA PET, 177Lu-PSMA-617, radioligand therapy, FOLH1, intergenic enhancers, differentially methylated regions, tumor microenvironment, molecular imaging, treatment resistance, precision medicine
- MeSH terms
- Antigens, Surface, Humans, Male, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Glutamate Carboxypeptidase II, Tumor Microenvironment, Prostatic Neoplasms, Castration-Resistant
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