Changes in prostate-specific membrane antigen (PSMA) expression following ionizing irradiation - Implications for prostate cancer therapy

Abstract: Targeted radionuclide therapy (TRT) has emerged as a valuable anticancer treatment in the past decade, as exemplified by the recent US and European regulatory approval of lutetium-177 (177Lu)-labeled PSMA-617 ([177Lu]Lu-PSMA-617) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The radiopharmaceutical targets prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer (PC). The outcomes of PSMA-TRT are highly dependent on the level of PSMA expression on the surface of the tumor cells suggesting that upregulating PSMA levels might be a promising strategy to improve therapy efficacy. Literature shows that PSMA expression can be modified by pharmacological agents and that the protein exerts functions in survival signaling and DNA repair. In this thesis, it was hypothesized that a combination of external beam radiotherapy (EBRT) and PSMA-TRT might improve therapeutic outcomes by escalating the radiation dose to the tumor and upregulating PSMA, consequently, increasing radiopharmaceutical uptake. The effects of external irradiation on PSMA expression in PC cells were analyzed to identify a suitable dose and time point for administration of PSMA-TRT. Additionally, the relevance of PSMA expression for radiosensitivity of PC cells was evaluated. An in vivo therapy study was conducted using a PC mouse model to examine the benefit of combining EBRT and PSMA-TRT.
High PSMA-expressing LNCaP cells were irradiated with 0.5-8 Gray (Gy) and changes in PSMA gene and protein expression were analyzed by reverse transcription quantitative polymerase chain reaction, flow cytometry and On-Cell Western assay. As compared to non-irradiated controls, a transient upregulation of PSMA levels on the cell surface by 18 % was observed at 4 h following irradiation with 2-8 Gy. This coincided with an increase in gene expression by up to 2.6-fold. However, the effect was short-lived as protein levels were downregulated by up to 22 % at 24 h post-irradiation. In irradiated tumor xenografts and in patient PC biopsies irradiated ex vivo, these effects were not reproduced. A possible reason might be that it was not differentiated between cytosolic and membranous PSMA expression in these experiments.
To analyze whether PSMA expression has radioprotective effects, PC cells were exposed to the PSMA inhibitor 2-phosphonomethyl pentanedioic acid (PMPA) and various endpoints were assessed. However, PSMA inhibition did not alter cell viability (resazurin assay), proliferation (3D growth assay), DNA damage and repair (γH2AX assay), and survival signaling (phosphorylation of Akt) in response to irradiation.
In the in vivo therapy study, BALB/c nu/nu mice bearing LNCaP tumor xenografts were first treated with 2 Gy EBRT and subsequently administered 40 Megabecquerel (MBq) [177Lu]Lu-PSMA-617 at 4h post-EBRT. The combination therapy significantly improved tumor control and median survival relative to the monotherapy or no treatment (p < 0.0001, n = 10 per group). The tumor doubling time with the combination therapy was 1.7- or 2.7-fold longer than with PSMA-TRT or EBRT alone. Interestingly, dosimetry studies using a gamma probe revealed a 14 % higher tumor-absorbed radiation dose by [177Lu]Lu-PSMA-617 in the group receiving the combination therapy as compared to the PSMA-TRT group. This indicates an increased radiopharmaceutical uptake after prior EBRT with, however, high variability in the data.
Collectively, these preclinical results suggest that the combination of EBRT and PSMA-TRT might improve the outcomes in PC treatment. The combination might be suitable for patients suffering from earlier stages of PC, such as oligo-metastatic disease, where it might improve the potential for a cure. The high interest in this therapeutic approach is reflected in several ongoing clinical trials

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Anmerkungen: Universität Freiburg, Dissertation, 2024

Klassifikation und Themen

• Schlagwort: Strahlentherapie ; Krebs ; DNS ; Prostatakrebs ; Strahlentherapie ; Prostataspezifisches Membranantigen

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2025
• Urheber: Arbuznikova, Daria
• Beteiligte Personen und Organisationen: Eder, Matthias ; Reinheckel, Thomas ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/263127
• URN: urn:nbn:de:bsz:25-freidok-2631270
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 15.08.2025, 07:20 MESZ