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Biomolecules
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Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine
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Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 25426

Special Issue Editor

Dr. Helen B. Pearson

E-Mail Website
Guest Editor
The European Cancer Stem Cell Research Insititute, Cardiff University, Cardiff, UK
Interests: prostate cancer; modeling disease; the PI3K pathway; cell signalling; preclinical trials and mechanisms of therapeutic resistance

Special Issue Information

Dear Colleagues,

Prostate cancer is a leading cause of cancer-related deaths in men, and increasing our understanding of the complex molecular mechanisms that contribute to prostate cancer promises to have a beneficial, global impact on our management of patients with prostate cancer. Valuable molecular insights are emerging through large-scale omics data and the development of diverse model systems that better recapitulate the different disease subtypes observed currently in the clinic. Together with technological advances,  these approaches have enabled pivotal preclinical studies that have better tailored the design of clinical trials, as well as functional genetic analysis of genes, or specific genetic alterations, to determine their functional consequence during tumor initiation, progression, and therapeutic resistance in a clinically relevant setting. These studies have been instrumental in delineating oncogenic cell signaling networks during prostate cancer growth, and uncovering a range of actionable targets and novel biomarkers that can accurately predict therapeutic responses, accelerating the field of precision medicine. 

This special issue aims to further understand the molecular mechanisms underpinning prostate cancer in relation to disease stage/subtypes, and highlight how advances in models of prostate cancer can build our understanding of prostate cancer biology and aid precision medicine.

We are pleased to invite you to submit a review article or original research articles in the field of prostate cancer. Suggested themes include exploring new insights into modelling this disease, improving our understanding of the underlying molecular mechanisms, identification of genetic drivers, actionable targets and/or biomarkers, and translational approaches of clinical relevance, including precision medicine.

I look forward to receiving your contributions.

Dr. Helen B. Pearson
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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • Models of disease
  • Cell signaling
  • Molecular mechanisms
  • Therapeutic resistance
  • Translational research
  • Precision medicine
  • Genetic drivers

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Published Papers (6 papers)

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Research

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14 pages, 64866 KiB  
Article
Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
by Sacha Genovesi, Riccardo Moro, Beatrice Vignoli, Dario De Felice, Marco Canossa, Rodolfo Montironi, Francesco Giuseppe Carbone, Mattia Barbareschi, Andrea Lunardi and Alessandro Alaimo
Biomolecules 2022, 12(2), 193; https://doi.org/10.3390/biom12020193 - 23 Jan 2022
Cited by 13 | Viewed by 4330
Abstract
Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which [...] Read more.
Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncurable. A definition of novel targeted therapies is necessary for the establishment of innovative and more effective protocols of personalized oncology. We employed genetically engineered mouse models of PCa and human samples to characterize the expression of the TRPM8 cation channel in both hormone naïve and castration resistant tumors. We show that Trpm8 expression marks both indolent (Pten-null) and aggressive (Pten/Trp53 double-null and TRAMP) mouse prostate adenocarcinomas. Importantly, both mouse and human castration-resistant PCa preserve TRPM8 protein expression. Finally, we tested the effect of TRPM8 agonist D-3263 administration in combination with enzalutamide or docetaxel on the viability of aggressive mouse PCa cell lines. Our data demonstrate that D-3263 substantially enhances the pro-apoptotic activity of enzalutamide and docetaxel in TRAMP-C1 e TRAMP-C2 PCa cell lines. To conclude, this study provides the basis for pre-clinical in vivo testing of TRPM8 targeting as a novel strategy to implement the efficacy of standard-of-care treatments for advanced PCa. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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14 pages, 5417 KiB  
Article
Dysregulation of DNA Methylation and Epigenetic Clocks in Prostate Cancer among Puerto Rican Men
by Anders Berglund, Jaime Matta, Jarline Encarnación-Medina, Carmen Ortiz-Sanchéz, Julie Dutil, Raymond Linares, Joshua Marcial, Caren Abreu-Takemura, Natasha Moreno, Ryan Putney, Ratna Chakrabarti, Hui-Yi Lin, Kosj Yamoah, Carlos Diaz Osterman, Liang Wang, Jasreman Dhillon, Youngchul Kim, Seung Joon Kim, Gilberto Ruiz-Deya and Jong Y. Park
Biomolecules 2022, 12(1), 2; https://doi.org/10.3390/biom12010002 - 21 Dec 2021
Cited by 5 | Viewed by 3307
Abstract
In 2021, approximately 248,530 new prostate cancer (PCa) cases are estimated in the United States. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. The objective of this study was to assess DNA methylation patterns between aggressive and indolent PCa along [...] Read more.
In 2021, approximately 248,530 new prostate cancer (PCa) cases are estimated in the United States. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. The objective of this study was to assess DNA methylation patterns between aggressive and indolent PCa along with ancestry proportions in 49 H/L men from Puerto Rico (PR). Prostate tumors were classified as aggressive (n = 17) and indolent (n = 32) based on the Gleason score. Genomic DNA samples were extracted by macro-dissection. DNA methylation patterns were assessed using the Illumina EPIC DNA methylation platform. We used ADMIXTURE to estimate global ancestry proportions. We identified 892 differentially methylated genes in prostate tumor tissues as compared with normal tissues. Based on an epigenetic clock model, we observed that the total number of stem cell divisions (TNSC) and stem cell division rate (SCDR) were significantly higher in tumor than adjacent normal tissues. Regarding PCa aggressiveness, 141 differentially methylated genes were identified. Ancestry proportions of PR men were estimated as African, European, and Indigenous American; these were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation profiles associated with risk and aggressiveness of PCa in PR H/L men will shed light on potential mechanisms contributing to PCa disparities in PR population. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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22 pages, 2634 KiB  
Article
Exploring the Value of BRD9 as a Biomarker, Therapeutic Target and Co-Target in Prostate Cancer
by Nafisa Barma, Timothy C. Stone, Lina Maria Carmona Echeverria and Susan Heavey
Biomolecules 2021, 11(12), 1794; https://doi.org/10.3390/biom11121794 - 30 Nov 2021
Cited by 5 | Viewed by 3564
Abstract
Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims [...] Read more.
Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterise BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA M.expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression, and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signalling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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15 pages, 5447 KiB  
Article
Modeling Prostate Cancer Treatment Responses in the Organoid Era: 3D Environment Impacts Drug Testing
by Annelies Van Hemelryk, Lisanne Mout, Sigrun Erkens-Schulze, Pim J. French, Wytske M. van Weerden and Martin E. van Royen
Biomolecules 2021, 11(11), 1572; https://doi.org/10.3390/biom11111572 - 22 Oct 2021
Cited by 11 | Viewed by 3873
Abstract
Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone [...] Read more.
Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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14 pages, 3649 KiB  
Article
Response Assessment and Prediction of Progression-Free Survival by 68Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy
by Fadi Khreish, Mona Wiessner, Florian Rosar, Zaidoon Ghazal, Amir Sabet, Stephan Maus, Johannes Linxweiler, Mark Bartholomä and Samer Ezziddin
Biomolecules 2021, 11(8), 1099; https://doi.org/10.3390/biom11081099 - 26 Jul 2021
Cited by 20 | Viewed by 2904
Abstract
At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and [...] Read more.
At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4–6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9–10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with 68Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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Review

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42 pages, 1981 KiB  
Review
Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer
by Sarah Koushyar, Valerie S. Meniel, Toby J. Phesse and Helen B. Pearson
Biomolecules 2022, 12(2), 309; https://doi.org/10.3390/biom12020309 - 15 Feb 2022
Cited by 21 | Viewed by 6320
Abstract
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence [...] Read more.
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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