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Open AccessEditorial

Editorial for the Special Edition of Advanced Prostate Cancer: From Bench to Bedside

by Fred Saad

Cancers 2023, 15(4), 1247; https://doi.org/10.3390/cancers15041247 - 16 Feb 2023

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Abstract

Prostate cancer is generally viewed as a slow-growing unaggressive cancer, yet it is one of the most commonly diagnosed cancers and a leading cause of morbidity and mortality in men around the world [...] Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

Research

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22 pages, 9869 KiB

Open AccessArticle

Co-Targeting ErbB Receptors and the PI3K/AKT Axis in Androgen-Independent Taxane-Sensitive and Taxane-Resistant Human Prostate Cancer Cells

by Samusi Adediran, Linbo Wang, Mohammad Afnan Khan, Wei Guang, Xiaoxuan Fan, Hancai Dan, Jianfei Qi, Steven M. Jay, France Carrier and Arif Hussain

Cancers 2022, 14(19), 4626; https://doi.org/10.3390/cancers14194626 - 23 Sep 2022

Cited by 3 | Viewed by 1948

Abstract

Using two representative models of androgen-independent prostate cancer (PCa), PC3 and DU145, and their respective paclitaxel- and docetaxel-resistant derivatives, we explored the anti-tumor activity of targeting the ErbB receptors and AKT using small-molecule kinase inhibitors. These cells manifest varying degrees of neuroendocrine differentiation [...] Read more.

Using two representative models of androgen-independent prostate cancer (PCa), PC3 and DU145, and their respective paclitaxel- and docetaxel-resistant derivatives, we explored the anti-tumor activity of targeting the ErbB receptors and AKT using small-molecule kinase inhibitors. These cells manifest varying degrees of neuroendocrine differentiation characteristics and differ in their expression of functional PTEN. Although the specific downstream signaling events post the ErbB receptor and AKT co-targeting varied between the PC3- and DU145-lineage cells, synergistic anti-proliferative and enhanced pro-apoptotic responses occurred across the wild-type and the taxane-resistant cells, independent of their basal AKT activation state, their degree of paclitaxel- or docetaxel-resistance, or whether this resistance was mediated by the ATP Binding Cassette transport proteins. Dual targeting also led to enhanced anti-tumor responses in vivo, although there was pharmacodynamic discordance between the PCa cells in culture versus the tumor xenografts in terms of the relative activation and inhibition states of AKT and ERK under basal conditions and upon AKT and/or ErbB targeting. The consistent inhibition, particularly of AKT, occurred both in vitro and in vivo, independent of the underlying PTEN status. Thus, co-targeting AKT with ErbB, and possibly other partners, may be a useful strategy to explore further for potential therapeutic effect in advanced PCa. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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21 pages, 3667 KiB

Open AccessArticle

High Keratin-7 Expression in Benign Peri-Tumoral Prostatic Glands Is Predictive of Bone Metastasis Onset and Prostate Cancer-Specific Mortality

by Charles Dariane, Sylvie Clairefond, Benjamin Péant, Laudine Communal, Zhe Thian, Véronique Ouellet, Dominique Trudel, Nazim Benzerdjeb, Feryel Azzi, Arnaud Méjean, Marc-Olivier Timsit, Manon Baurès, Jacques-Emmanuel Guidotti, Vincent Goffin, Pierre I. Karakiewicz, Anne-Marie Mes-Masson and Fred Saad

Cancers 2022, 14(7), 1623; https://doi.org/10.3390/cancers14071623 - 23 Mar 2022

Cited by 8 | Viewed by 2823

Abstract

Background: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in [...] Read more.

Background: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in the mouse prostate. Methods: KRT7 expression was evaluated in prostatic cell lines and in human tissue by immunohistochemistry (IHC, on advanced PC, n = 91) and immunofluorescence (IF, on localized PC, n = 285). The KRT7 mean fluorescence intensity (MFI) was quantified in different compartments by digital analysis and correlated to clinical endpoints in the localized PC cohort. Results: KRT7 is expressed in prostatic cell lines and found in the basal and supra-basal compartment from healthy prostatic glands and benign peri-tumoral glands from localized PC. The KRT7 staining is lost in luminal cells from localized tumors and found as an aberrant sporadic staining (2.2%) in advanced PC. In the localized PC cohort, high KRT7 MFI above the 80th percentile in the basal compartment was significantly and independently correlated with MFS and CSS, and with hypertrophic basal cell phenotype. Conclusion: High KRT7 expression in benign glands is an independent biomarker of MFS and CSS, and its expression is lost in tumoral cells. These results require further validation on larger cohorts. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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14 pages, 2270 KiB

Open AccessArticle

Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

by T. Hedley Carr, Carrie Adelman, Alan Barnicle, Iwanka Kozarewa, Sally Luke, Zhongwu Lai, Sally Hollis, Brian Dougherty, Elizabeth A. Harrington, Jinyu Kang, Fred Saad, Nuria Sala, Antoine Thiery-Vuillemin, Noel W. Clarke, Darren Hodgson and J. Carl Barrett

Cancers 2021, 13(22), 5830; https://doi.org/10.3390/cancers13225830 - 20 Nov 2021

Cited by 20 | Viewed by 5989

Abstract

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs [...] Read more.

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (n = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (n = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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12 pages, 4051 KiB

Open AccessArticle

Glyoxalase 1 Expression as a Novel Diagnostic Marker of High-Grade Prostatic Intraepithelial Neoplasia in Prostate Cancer

by Liliana Rounds, Ray B. Nagle, Andrea Muranyi, Jana Jandova, Scott Gill, Elizabeth Vela and Georg T. Wondrak

Cancers 2021, 13(14), 3608; https://doi.org/10.3390/cancers13143608 - 19 Jul 2021

Cited by 9 | Viewed by 3008

Abstract

Glyoxalase 1 (GLO1) is an enzyme involved in the detoxification of methylglyoxal (MG), a reactive oncometabolite formed in the context of energy metabolism as a result of high glycolytic flux. Prior clinical evidence has documented GLO1 upregulation in various tumor types including prostate [...] Read more.

Glyoxalase 1 (GLO1) is an enzyme involved in the detoxification of methylglyoxal (MG), a reactive oncometabolite formed in the context of energy metabolism as a result of high glycolytic flux. Prior clinical evidence has documented GLO1 upregulation in various tumor types including prostate cancer (PCa). However, GLO1 expression has not been explored in the context of PCa progression with a focus on high-grade prostatic intraepithelial neoplasia (HGPIN), a frequent precursor to invasive cancer. Here, we have evaluated GLO1 expression by immunohistochemistry in archival tumor samples from 187 PCa patients (stage 2 and 3). Immunohistochemical analysis revealed GLO1 upregulation during tumor progression, observable in HGPIN and PCa versus normal prostatic tissue. GLO1 upregulation was identified as a novel hallmark of HGPIN lesions, displaying the highest staining intensity in all clinical patient specimens. GLO1 expression correlated with intermediate–high risk Gleason grade but not with patient age, biochemical recurrence, or pathological stage. Our data identify upregulated GLO1 expression as a molecular hallmark of HGPIN lesions detectable by immunohistochemical analysis. Since current pathological assessment of HGPIN status solely depends on morphological features, GLO1 may serve as a novel diagnostic marker that identifies this precancerous lesion. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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Review

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12 pages, 262 KiB

Open AccessReview

Targeted Approaches in Metastatic Castration-Resistant Prostate Cancer: Which Data?

by Claudia Mosillo, Maria Letizia Calandrella, Claudia Caserta, Serena Macrini, Annalisa Guida, Grazia Sirgiovanni and Sergio Bracarda

Cancers 2022, 14(17), 4189; https://doi.org/10.3390/cancers14174189 - 29 Aug 2022

Cited by 6 | Viewed by 1971

Abstract

Prostate cancer is the second most common diagnosed cancer and the fifth leading cause of cancer-related deaths in men worldwide. Despite significant advances in the management of castration-sensitive prostate cancer, the majority of patients develop a castration-resistant disease after a median duration of [...] Read more.

Prostate cancer is the second most common diagnosed cancer and the fifth leading cause of cancer-related deaths in men worldwide. Despite significant advances in the management of castration-sensitive prostate cancer, the majority of patients develop a castration-resistant disease after a median duration of treatment of 18–48 months. The transition to a castrate resistance state could rely on alternative survival pathways, some related to androgen-independent mechanisms. Although several agents have been approved in this setting, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Recent studies revealed some of the complex pathways underlying inherited and acquired mechanisms of resistance to available treatments. A better understanding of these pathways may lead to significant improvements in survival by providing innovative therapeutic targets. The present comprehensive review attempts to provide an overview of recent progress in novel targeted therapies and near-future directions. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

19 pages, 523 KiB

Open AccessReview

Where Do We Stand in the Management of Oligometastatic Prostate Cancer? A Comprehensive Review

by Gómez Rivas Juan, Fernández Hernández Laura, Puente Vázquez Javier, Vidal Casinello Natalia, Galante Romo Mᵃ Isabel, Redondo González Enrique, Senovilla Pérez José Luis, Abad López Pablo, Sanmamed Salgado Noelia, Vives Dilme Roser and Moreno-Sierra Jesús

Cancers 2022, 14(8), 2017; https://doi.org/10.3390/cancers14082017 - 16 Apr 2022

Cited by 9 | Viewed by 4634

Abstract

Oligometastatic prostate cancer (OMPC) is an intermediate state between localised disease and widespread metastases that includes a spectrum of disease biology and clinical behaviours. This narrative review will cover the current OMPC scenario. We conducted comprehensive English language literature research for original and [...] Read more.

Oligometastatic prostate cancer (OMPC) is an intermediate state between localised disease and widespread metastases that includes a spectrum of disease biology and clinical behaviours. This narrative review will cover the current OMPC scenario. We conducted comprehensive English language literature research for original and review articles using the Medline database and grey literature through December 2021. OMPC is a unique clinical state with inherently more indolent tumour biology susceptible to multidisciplinary treatment (MDT). With the development of new imaging techniques, patients with OMPC are likely to be identified at an earlier stage, and the paradigm for treatment is shifting towards a more aggressive approach to treating potentially curable patients. Multimodal management is necessary to improve patient outcomes due to the combination of available therapies, such as local therapy of primary tumour, metastasis directed therapy or systemic therapy, to reduce tumour load and prevent further disease progression. Additional prospective data are needed to select patients most likely to benefit from a given therapeutic approach. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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14 pages, 266 KiB

Open AccessReview

Clinical Management of Prostate Cancer in High-Risk Genetic Mutation Carriers

by Roderick Clark, Jaime Herrera-Caceres, Miran Kenk and Neil Fleshner

Cancers 2022, 14(4), 1004; https://doi.org/10.3390/cancers14041004 - 16 Feb 2022

Cited by 8 | Viewed by 2845

Abstract

Background: Prostate cancer is a leading cause of death. Approximately one in eight men who are diagnosed with prostate cancer will die of it. Since there is a large difference in mortality between low- and high-risk prostate cancers, it is critical to identify [...] Read more.

Background: Prostate cancer is a leading cause of death. Approximately one in eight men who are diagnosed with prostate cancer will die of it. Since there is a large difference in mortality between low- and high-risk prostate cancers, it is critical to identify individuals who are at high-risk for disease progression and death. Germline genetic differences are increasingly recognized as contributing to risk of lethal prostate cancer. The objective of this paper is to review prostate cancer management options for men with high-risk germline mutations. Methods: We performed a review of the literature to identify articles regarding management of prostate cancer in individuals with high-risk germline genetic mutations. Results: We identified numerous publications regarding the management of prostate cancer among high-risk germline carriers, but the overall quality of the evidence is low. Conclusions: We performed a review of the literature and compiled clinical considerations for the management of individuals with high-risk germline mutations when they develop prostate cancer. The quality of the evidence is low, and there is an immediate need for further research and the development of consensus guidelines to guide clinical practice for these individuals. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

13 pages, 1038 KiB

Open AccessReview

Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer—Where Are We Now?

by Arpit Rao, Nagaishwarya Moka, Daniel A. Hamstra and Charles J. Ryan

Cancers 2022, 14(3), 801; https://doi.org/10.3390/cancers14030801 - 4 Feb 2022

Cited by 28 | Viewed by 4489

Abstract

Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, [...] Read more.

Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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13 pages, 943 KiB

Open AccessReview

Ethnic Pharmacogenomic Differences in the Management of Asian Patients with Metastatic Prostate Cancer

by Darren M. C. Poon, Kuen Chan, Tim Chan, Foo-Yiu Cheung, Daisy Lam, Martin Lam, Ka-Suet Law, Conrad Lee, Eric K. C. Lee, Angus Leung, Henry Sze, Chi-Chung Tong, Kenneth C. W. Wong and Philip Kwong

Cancers 2022, 14(2), 407; https://doi.org/10.3390/cancers14020407 - 14 Jan 2022

Cited by 5 | Viewed by 2988

Abstract

Progression to metastatic disease occurs in about half of all men who develop prostate cancer (PC), one of the most common cancers in men worldwide. Androgen deprivation therapy has been the mainstay therapy for patients with metastatic PC (mPC) since the 1940s. In [...] Read more.

Progression to metastatic disease occurs in about half of all men who develop prostate cancer (PC), one of the most common cancers in men worldwide. Androgen deprivation therapy has been the mainstay therapy for patients with metastatic PC (mPC) since the 1940s. In the last decade, there has been unprecedented advancement in systemic therapies, e.g., taxane, androgen-signalling pathway inhibitors, and biomarker-driven targeted therapies for various stages of disease, resulting in overall survival improvement. Adding to ongoing controversies over how best to treat these patients is the recognition that ethnicity may influence prognosis and outcomes. This review discusses recent evidence for the impacts of Asian ethnicity specifically, which includes environmental, sociocultural, and genetic factors, on the approach to pharmacological management of mPC. Clear inter-ethnic differences in drug tolerability, serious adverse events (AEs), and genetic heterogeneity must all be considered when dosing and scheduling for treatment, as well as designing future precision studies in PC. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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26 pages, 2122 KiB

Open AccessReview

Targeting the Intrinsic Apoptosis Pathway: A Window of Opportunity for Prostate Cancer

by Daniel Westaby, Juan M. Jimenez-Vacas, Ana Padilha, Andreas Varkaris, Steven P. Balk, Johann S. de Bono and Adam Sharp

Cancers 2022, 14(1), 51; https://doi.org/10.3390/cancers14010051 - 23 Dec 2021

Cited by 23 | Viewed by 6651

Abstract

Despite major improvements in the management of advanced prostate cancer over the last 20 years, the disease remains invariably fatal, and new effective therapies are required. The development of novel hormonal agents and taxane chemotherapy has improved outcomes, although primary and acquired resistance [...] Read more.

Despite major improvements in the management of advanced prostate cancer over the last 20 years, the disease remains invariably fatal, and new effective therapies are required. The development of novel hormonal agents and taxane chemotherapy has improved outcomes, although primary and acquired resistance remains problematic. Inducing cancer cell death via apoptosis has long been an attractive goal in the treatment of cancer. Apoptosis, a form of regulated cell death, is a highly controlled process, split into two main pathways (intrinsic and extrinsic), and is stimulated by a multitude of factors, including cellular and genotoxic stress. Numerous therapeutic strategies targeting the intrinsic apoptosis pathway are in clinical development, and BH3 mimetics have shown promising efficacy for hematological malignancies. Utilizing these agents for solid malignancies has proved more challenging, though efforts are ongoing. Molecular characterization and the development of predictive biomarkers is likely to be critical for patient selection, by identifying tumors with a vulnerability in the intrinsic apoptosis pathway. This review provides an up-to-date overview of cell death and apoptosis, specifically focusing on the intrinsic pathway. It summarizes the latest approaches for targeting the intrinsic apoptosis pathway with BH3 mimetics and discusses how these strategies may be leveraged to treat prostate cancer. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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15 pages, 310 KiB

Open AccessReview

A Review on the Current Treatment Paradigm in High-Risk Prostate Cancer

by Laura Burgess, Soumyajit Roy, Scott Morgan and Shawn Malone

Cancers 2021, 13(17), 4257; https://doi.org/10.3390/cancers13174257 - 24 Aug 2021

Cited by 13 | Viewed by 4667

Abstract

High-risk prostate cancer is traditionally treated with a combination of radiotherapy (RT) and androgen deprivation therapy (ADT). However, recent advancements in systemic treatment and radiotherapy have widened the spectrum of treatment for this patient population. Use of image guidance and intensity modulation, as [...] Read more.

High-risk prostate cancer is traditionally treated with a combination of radiotherapy (RT) and androgen deprivation therapy (ADT). However, recent advancements in systemic treatment and radiotherapy have widened the spectrum of treatment for this patient population. Use of image guidance and intensity modulation, as well as the incorporation of brachytherapy, has led to safe radiotherapy dose escalation with reduced risk of recurrence. Clinical trials have helped define the role of pelvic nodal radiotherapy, the role of stereotactic ablative radiotherapy, and the optimal duration and sequencing of ADT in combination with radiotherapy. Emerging evidence has redefined the role of surgery in this cohort. Contemporary clinical trials have identified new systemic therapy options in high-risk prostate cancer. Finally, new imaging modalities including multi-parametric MRI and molecular imaging and genomic classifiers have ushered a new era in patient selection, risk stratification, and treatment tailoring. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

17 pages, 699 KiB

Open AccessReview

PSMA Theranostics: Current Landscape and Future Outlook

by Hanbo Zhang, Stella Koumna, Frédéric Pouliot, Jean-Mathieu Beauregard and Michael Kolinsky

Cancers 2021, 13(16), 4023; https://doi.org/10.3390/cancers13164023 - 10 Aug 2021

Cited by 39 | Viewed by 11169

Abstract

Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history. Methods: [...] Read more.

Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history. Methods: We utilized PubMed and Google Scholar for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic clinical trials throughout the various stages of prostate cancer. Conclusions: In this review, we presented the contemporary and future landscape of theranostic applications in prostate cancer with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for the management of prostate cancer, we underscore the importance of integrating nuclear medicine physicians into the multidisciplinary team. Full article

(This article belongs to the Special Issue Advanced Prostate Cancer: From Bench to Bedside)

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