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PSMA in Prostate Cancer
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PSMA in Prostate Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 32031

Special Issue Editor

Dr. Finn Edler von Eyben

E-Mail Website
Guest Editor
Center of Tobacco Control Research, 5230 Odense, Denmark
Interests: cancer biology; urologic oncology; tumor markers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prostate Cancer has the second highest mortality for men in Western Societies. Prostate Specific Membrane Antigen (PSMA) is a glycoprotein that is highly expressed in plasma membrane of prostate cancer especially in the most aggressive forms for prostate cancer. In the recent decade PSMA PET/CT has become widely used in diagnostics of patients with metastatic castration-resistant prostate cancer (mCRPC). PSMA PET/CT has a high detection rate even for patients with low values of prostate specific antigen (PSA). Staging with PSMA PET/CT change planned treatment for more than a quarter of the patients. Radioligands can bind to the extracellular part of PSMA. Thereby the radioligand is absorbed into the cancer cells and damage the DNA of the cells. PSMA radioligand therapy is a safe and effective treatment of patients with metastatic castration-resistant prostate cancer as documented in two published randomized controlled trials, the TheraP and VISION trials. This issue of International Journal of Molecular Sciences provides up-to-date information on the use of PSMA for diagnostics and treatment of patients with prostate cancer. The issue serves as a very useful resource tool for patients, physicians, and researchers dealing with the challenge of mCRPC.

This issue has a joint special issue (https://www.mdpi.com/journal/diagnostics/special_issues/PSMA_diag) with our sister journal /Diagnostics/ (ISSN 2075-4418, IF: 3.110, https://www.mdpi.com/journal/diagnostics). For papers focused on molecular science are encouraged to submit to IJMS, for others to Diagnostics.

Dr. Finn Edler von Eyben
Guest Editor

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Keywords

  • prospective studies
  • prostate cancer
  • retrospective studies
  • reviews
  • tumor biology
  • theranostics

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 176 KiB  
Editorial
On the Way for Patients with Prostate Cancer to the Best Use of PSMA
by Finn Edler von Eyben, Glenn Bauman, Daniel S. Kapp, Irene Virgolini and Giovanni Paganelli
Int. J. Mol. Sci. 2022, 23(5), 2478; https://doi.org/10.3390/ijms23052478 - 24 Feb 2022
Viewed by 1702
Abstract
In recent years, the prostate-specific membrane antigen (PSMA) has achieved a significant role in the diagnostics and treatments of patients with prostate cancer [...] Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)

Research

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17 pages, 1454 KiB  
Article
Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists
by Sashi Debnath, Guiyang Hao, Bing Guan, Pawan Thapa, Justin Hao, Hans Hammers and Xiankai Sun
Int. J. Mol. Sci. 2022, 23(13), 7160; https://doi.org/10.3390/ijms23137160 - 28 Jun 2022
Cited by 18 | Viewed by 4025
Abstract
We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody–drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal [...] Read more.
We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody–drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA− PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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17 pages, 1875 KiB  
Article
Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells
by Ulrich Sommer, Tiziana Siciliano, Celina Ebersbach, Alicia-Marie K. Beier, Matthias B. Stope, Korinna Jöhrens, Gustavo B. Baretton, Angelika Borkowetz, Christian Thomas and Holger H. H. Erb
Int. J. Mol. Sci. 2022, 23(3), 1046; https://doi.org/10.3390/ijms23031046 - 18 Jan 2022
Cited by 15 | Viewed by 4165
Abstract
Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a [...] Read more.
Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a resistance mechanism to PSMA-based imaging and therapy. Clinical studies revealed that androgen receptor (AR) inhibition increases PSMA expression. The mechanism has not yet been elucidated. Therefore, this study investigated the effect of activation and inhibition of androgen signaling on PSMA expression levels in vitro and compared these findings with PSMA levels in PCa patients receiving systemic therapy. To this end, LAPC4, LNCaP, and C4-2 PCa cells were treated with various concentrations of the synthetic androgen R1881 and antiandrogens. Changes in FOLH1 mRNA were determined using qPCR. Open access databases were used for ChIP-Seq and tissue expression analysis. Changes in PSMA protein were determined using western blot. For PSMA staining in patients’ specimens, immunohistochemistry (IHC) was performed. Results revealed that treatment with the synthetic androgen R1881 led to decreased FOLH1 mRNA and PSMA protein. This effect was partially reversed by antiandrogen treatment. However, AR ChIP-Seq analysis revealed no canonical AR binding sites in the regulatory elements of the FOLH1 gene. IHC analysis indicated that androgen deprivation only resulted in increased PSMA expression in patients with low PSMA levels. The data demonstrate that AR activation and inhibition affects PSMA protein levels via a possible non-canonical mechanism. Moreover, analysis of PCa tissue reveals that low PSMA expression rates may be mandatory to increase PSMA by androgen deprivation. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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12 pages, 1874 KiB  
Communication
Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer
by Magdalena Staniszewska, Pedro Fragoso Costa, Matthias Eiber, Jasmin M. Klose, Jasmin Wosniack, Henning Reis, Tibor Szarvas, Boris Hadaschik, Katharina Lückerath, Ken Herrmann, Wolfgang P. Fendler and Janette Iking
Int. J. Mol. Sci. 2021, 22(14), 7431; https://doi.org/10.3390/ijms22147431 - 11 Jul 2021
Cited by 29 | Viewed by 6678
Abstract
Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of [...] Read more.
Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of PSMA and androgen receptor (AR) expression on the human PC cell lines 22Rv1, C4-2, and LNCaP by immunohistochemistry and flow cytometry revealed low (22Rv1) and high (C4-2 and LNCaP) PSMA expression, and high, comparable AR positivity. Treatment with enzalutamide increased PSMA levels in 22Rv1, C4-2, and LNCaP (2.2/2.3/2.6-fold, p = 0.0005/0.03/0.046) after one week compared to DMSO-treated controls as assessed by flow cytometry. NOD/Scid mice bearing 22Rv1 tumors were treated with enzalutamide for two weeks. Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68Ga-PSMA after enzalutamide treatment (p = 0.004). Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177Lu-PSMA scintigraphy in a patient with mCRPC. Enzalutamide induced PSMA expression in the 22Rv1 xenograft model and in an mCRPC patient, both with low baseline tumoral PSMA levels. Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177Lu-PSMA RLT. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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18 pages, 8077 KiB  
Article
Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer
by Vilde Yuli Stenberg, Roy Hartvig Larsen, Li-Wei Ma, Qian Peng, Petras Juzenas, Øyvind Sverre Bruland and Asta Juzeniene
Int. J. Mol. Sci. 2021, 22(9), 4815; https://doi.org/10.3390/ijms22094815 - 1 May 2021
Cited by 21 | Viewed by 4373
Abstract
Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical [...] Read more.
Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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Review

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19 pages, 1666 KiB  
Review
PSMA-Targeting Imaging and Theranostic Agents—Current Status and Future Perspective
by Sashi Debnath, Ning Zhou, Mark McLaughlin, Samuel Rice, Anil K. Pillai, Guiyang Hao and Xiankai Sun
Int. J. Mol. Sci. 2022, 23(3), 1158; https://doi.org/10.3390/ijms23031158 - 21 Jan 2022
Cited by 50 | Viewed by 5545
Abstract
In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States [...] Read more.
In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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17 pages, 2051 KiB  
Review
Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis
by Finn Edler von Eyben, Glenn Bauman, Rie von Eyben, Kambiz Rahbar, Cigdem Soydal, Alexander R. Haug, Irene Virgolini, Harshad Kulkarni, Richard Baum and Giovanni Paganelli
Int. J. Mol. Sci. 2020, 21(23), 9054; https://doi.org/10.3390/ijms21239054 - 28 Nov 2020
Cited by 30 | Viewed by 4174
Abstract
The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for [...] Read more.
The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of 177Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT. Full article
(This article belongs to the Special Issue PSMA in Prostate Cancer)
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