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Advances in Prostate Cancer Diagnostics and Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 July 2024 | Viewed by 7465

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Special Issue Editor

Dr. Benedikt Kranzbühler

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Guest Editor

Department of Urology, University Hospital Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland
Interests: prostate-specific membrane antigen (PSMA); prostate cancer; molecular imaging; reconstructive urology

Special Issue Information

Dear Colleagues,

Prostate cancer is still the second most commonly diagnosed cancer in men and accounts for 1.4 million diagnoses worldwide. Despite recent advances in diagnostics and treatment of prostate cancer, many questions remain unanswered. Prostate-specific membrane antigen-based imaging and therapy is a promising, quickly evolving field of research. Notably, patients with early biochemical recurrence might benefit from improved imaging prior to salvage therapy. In addition, studies have shown promising results in patients with advanced metastatic disease. However, many molecular pathways and their interaction with the androgen receptor are not yet fully elucidated. This Special Issue of the International Journal of Molecular Sciences will focus on recent “Advances in Prostate Cancer Diagnostics and Therapy”, including new insights into pathogenesis and molecular pathways. Submissions dealing with biomarkers, molecular pathways, improvements in prostate cancer imaging, and therapy are highly welcome.

Dr. Benedikt Kranzbühler
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

prostate cancer
molecular pathways
diagnostics
therapy

Published Papers (6 papers)

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Research

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16 pages, 586 KiB

Open AccessArticle

Integrative Metabolomic Analysis of Serum and Selected Serum Exosomal microRNA in Metastatic Castration-Resistant Prostate Cancer

by Daniel Evin, Andrea Evinová, Eva Baranovičová, Miroslava Šarlinová, Jana Jurečeková, Peter Kaplán, Hubert Poláček, Erika Halašová, Róbert Dušenka, Lukáš Briš, Martina Knoško Brožová and Monika Kmeťová Sivoňová

Int. J. Mol. Sci. 2024, 25(5), 2630; https://doi.org/10.3390/ijms25052630 - 23 Feb 2024

Viewed by 872

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease due to the absence of effective therapies. A more comprehensive understanding of molecular events, encompassing the dysregulation of microRNAs (miRs) and metabolic reprogramming, holds the potential to unveil precise mechanisms underlying mCRPC. This study aims to assess the expression of selected serum exosomal miRs (miR-15a, miR-16, miR-19a-3p, miR-21, and miR-141a-3p) alongside serum metabolomic profiling and their correlation in patients with mCRPC and benign prostate hyperplasia (BPH). Blood serum samples from mCRPC patients (n = 51) and BPH patients (n = 48) underwent metabolome analysis through ¹H-NMR spectroscopy. The expression levels of serum exosomal miRs in mCRPC and BPH patients were evaluated using a quantitative real-time polymerase chain reaction (qRT-PCR). The ¹H-NMR metabolomics analysis revealed significant alterations in lactate, acetate, citrate, 3-hydroxybutyrate, and branched-chain amino acids (BCAAs, including valine, leucine, and isoleucine) in mCRPC patients compared to BPH patients. MiR-15a, miR-16, miR-19a-3p, and miR-21 exhibited a downregulation of more than twofold in the mCRPC group. Significant correlations were predominantly observed between lactate, citrate, acetate, and miR-15a, miR-16, miR-19a-3p, and miR-21. The importance of integrating metabolome analysis of serum with selected serum exosomal miRs in mCRPC patients has been confirmed, suggesting their potential utility for distinguishing of mCRPC from BPH. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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17 pages, 8734 KiB

Open AccessArticle

Development and Characterization of ^99mTc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer

by Cristina Bolzati, Carolina Gobbi, Guillermina Ferro-Flores, Sofia Turato, Blanca Ocampo-Garcia, Debora Carpanese, Cristina Marzano, Barbara Spolaore, Giulio Fracasso, Antonio Rosato and Laura Meléndez-Alafort

Int. J. Mol. Sci. 2024, 25(1), 492; https://doi.org/10.3390/ijms25010492 - 29 Dec 2023

Viewed by 833

Abstract

Previously, we demonstrated that the ¹⁷⁷Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) cell uptake and tumor radiation doses compared to ¹⁷⁷Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a ^99mTc-/¹⁷⁷Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel ^99mTc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified. Then, two HYNIC derivatives, HYNIC-Gly-Gly-Cys-NH₂ (HYNIC-GGC) and succinimidyl-HYNIC (S-HYNIC), were used to conjugate the scFvD2B-Tag and scFvD2B isoforms, respectively. Subsequently, chemical characterization, immunoreactivity tests (affinity and specificity), radiochemical purity tests, stability tests in human serum, cellular uptake and internalization in LNCaP(+), PC3-PIP(++) or PC3(−) PCa cells of the resulting unlabeled HYNIC-scFvD2B conjugates (HscFv) and ^99mTc-HscFv agents were performed. The results showed that incorporating HYNIC as a chelator did not affect the affinity, specificity or stability of scFvD2B. After purification, the radiochemical purity of ^99mTc-HscFv radiotracers was greater than 95%. A two-sample t-test of ^99mTc-HscFv1 and ^99mTc-HscFv1 uptake in PC3-PIP vs. PC3 showed a p-value < 0.001, indicating that the PSMA receptor interaction of ^99mTc-HscFv agents was statistically significantly higher in PSMA-positive cells than in the negative controls. In conclusion, the results of this research warrant further preclinical studies to determine whether the in vivo pharmacokinetics and tumor uptake of ^99mTc-HscFv still offer sufficient advantages over HYNIC-conjugated peptides to be considered for SPECT/PSMA imaging. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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19 pages, 3619 KiB

Open AccessArticle

Unveiling the Molecular Landscape of FOXA1 Mutant Prostate Cancer: Insights and Prospects for Targeted Therapeutic Strategies

by Kyung Won Hwang, Jae Won Yun and Hong Sook Kim

Int. J. Mol. Sci. 2023, 24(21), 15823; https://doi.org/10.3390/ijms242115823 - 31 Oct 2023

Viewed by 1290

Abstract

Prostate cancer continues to pose a global health challenge as one of the most prevalent malignancies. Mutations of the Forkhead box A1 (FOXA1) gene have been linked to unique oncogenic features in prostate cancer. In this study, we aimed to unravel the intricate molecular characteristics of FOXA1 mutant prostate cancer through comprehensive in silico analysis of transcriptomic data from The Cancer Genome Atlas (TCGA). A comparison between FOXA1 mutant and control groups unearthed 1525 differentially expressed genes (DEGs), which map to eight intrinsic and six extrinsic signaling pathways. Interestingly, the majority of intrinsic pathways, but not extrinsic pathways, were validated using RNA-seq data of 22Rv1 cells from the GEO123619 dataset, suggesting complex biology in the tumor microenvironment. As a result of our in silico research, we identified novel therapeutic targets and potential drug candidates for FOXA1 mutant prostate cancer. KDM1A, MAOA, PDGFB, and HSP90AB1 emerged as druggable candidate targets, as we found that they have approved drugs throughout the drug database CADDIE. Notably, as most of the approved drugs targeting MAOA and KDM1A were monoamine inhibitors used for mental illness or diabetes, we suggest they have a potential to cure FOXA1 mutant primary prostate cancer without lethal side effects. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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19 pages, 6008 KiB

Open AccessArticle

Assessing the Potential of Small Peptides for Altering Expression Levels of the Iron-Regulatory Genes FTH1 and TFRC and Enhancing Androgen Receptor Inhibitor Activity in In Vitro Prostate Cancer Models

by Crawford Currie, Christian Bjerknes, Tor Åge Myklebust and Bomi Framroze

Int. J. Mol. Sci. 2023, 24(20), 15231; https://doi.org/10.3390/ijms242015231 - 16 Oct 2023

Viewed by 1261

Abstract

Recent research highlights the key role of iron dyshomeostasis in the pathogenesis of prostate cancer (PCa). PCa cells are heavily dependent on bioavailable iron, which frequently results in the reprogramming of iron uptake and storage pathways. Although advanced-stage PCa is currently incurable, bioactive peptides capable of modulating key iron-regulatory genes may constitute a means of exploiting a metabolic adaptation necessary for tumor growth. Recent annual increases in PCa incidence have been reported, highlighting the urgent need for novel treatments. We examined the ability of LNCaP, PC3, VCaP, and VCaP-EnzR cells to form colonies in the presence of androgen receptor inhibitors (ARI) and a series of iron-gene modulating oligopeptides (FT-001-FT-008). The viability of colonies following treatment was determined with clonogenic assays, and the expression levels of FTH1 (ferritin heavy chain 1) and TFRC (transferrin receptor) were determined with quantitative polymerase chain reaction (PCR). Peptides and ARIs combined significantly reduced PCa cell growth across all phenotypes, of which two peptides were the most effective. Colony growth suppression generally correlated with the magnitude of concurrent increases in FTH1 and decreases in TFRC expression for all cells. The results of this study provide preliminary insight into a novel approach at targeting iron dysmetabolism and sensitizing PCa cells to established cancer treatments. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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Graphical abstract

15 pages, 4836 KiB

Open AccessArticle

Improved Prostate-Specific Membrane Antigen (PSMA) Stimulation Using a Super Additive Effect of Dutasteride and Lovastatin In Vitro

by Aleksandar Kuzmanov, Souzan Salemi, Florian A. Schmid, Irene A. Burger, Daniel Eberli and Benedikt Kranzbühler

Int. J. Mol. Sci. 2023, 24(15), 12338; https://doi.org/10.3390/ijms241512338 - 02 Aug 2023

Viewed by 1603

Abstract

Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low PSMA surface expression can be a limitation for this promising diagnostic tool. Pharmacological induction of PSMA might be useful to further improve the detection rate of PSMA-based imaging. To achieve this, we tested dutasteride (Duta)—generally used for treatment of benign prostatic enlargement—and lovastatin (Lova)—a compound used to reduce blood lipid concentrations. We aimed to compare the individual effects of Duta and Lova on cell proliferation as well as PSMA expression. In addition, we tested if a combination treatment using lower concentrations of Duta and Lova can further induce PSMA expression. Our results show that a treatment with ≤1 μM Duta and ≥1 μM Lova lead to a significant upregulation of whole and cell surface PSMA expression in LNCaP, C4-2 and VCaP cells. Lower concentrations of Duta and Lova in combination (0.5 μM Duta + 0.5 μM Lova or 0.5 μM Duta + 1 μM Lova) were further capable of enhancing PSMA protein expression compared to a single compound treatment using higher concentrations in all tested cell lines (LNCaP, C4-2 and VCaP). Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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Review

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21 pages, 4684 KiB

Open AccessReview

Preoperative Factors for Lymphovascular Invasion in Prostate Cancer: A Systematic Review and Meta-Analysis

by Jakub Karwacki, Marcel Stodolak, Łukasz Nowak, Paweł Kiełb, Wojciech Krajewski, Artur Lemiński, Tomasz Szydełko and Bartosz Małkiewicz

Int. J. Mol. Sci. 2024, 25(2), 856; https://doi.org/10.3390/ijms25020856 - 10 Jan 2024

Cited by 1 | Viewed by 872

Abstract

Lymphovascular invasion (LVI) is one of the most important prognostic factors in prostate cancer (PCa) and is correlated with worse survival rates, biochemical recurrence (BCR), and lymph node metastasis (LNM). The ability to predict LVI preoperatively in PCa may be useful for proposing variations in the diagnosis and management strategies. We performed a systematic review and meta-analysis to identify preoperative clinicopathological factors that correlate with LVI in final histopathological specimens in PCa patients. Systematic literature searches of PubMed, Embase, and Web of Science were performed up to 31 January 2023. A total of thirty-nine studies including 389,918 patients were included, most of which were retrospective and single-center. PSA level, clinical T stage, and biopsy Gleason score were significantly correlated with LVI in PCa specimens. Meta-analyses revealed that these factors were the strongest predictors of LVI in PCa patients. Prostate volume, BMI, and age were not significant predictors of LVI. A multitude of preoperative factors correlate with LVI in final histopathology. Meta-analyses confirmed correlation of LVI in final histopathology with higher preoperative PSA, clinical T stage, and biopsy Gleason score. This study implies advancements in risk stratification and enhanced clinical decision-making, and it underscores the importance of future research dedicated to validation and exploration of contemporary risk factors in PCa. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Diagnostics and Therapy)

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