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Cancers
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Advances in Companion Biomarker Development for Prostate Cancer
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Advances in Companion Biomarker Development for Prostate Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 15965

Special Issue Editors

Prof. Lisa M. Butler

E-Mail Website
Guest Editor
Adelaide Medical School, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, Australia
Interests: prostate cancer; biomarker discovery; lipid metabolism
Prof. Lisa G. Horvath

E-Mail Website
Guest Editor
Chris O’Brien Lifehouse and Garvan Institute of Medical Research, Sydney, Australia
Interests: medical oncology; clinical trials; biomarker discovery; lipid metabolism

Special Issue Information

Dear Colleagues,

Key to improving the survival rates for prostate cancer is the development of effective new systemic agents in parallel with biomarkers that either identify patients who are likely to respond or can be used to evaluate patient response during treatment. Indeed, the lack of a biomarker-driven strategy and failure to achieve “proof of concept” in Phase 2 trials are significant contributors in cancer drugs failing to achieve clinical success, including FDA approval. In recent years, biomarker discovery has moved beyond genomic tumour features to incorporate circulating analytes, such as non-coding RNAs, cell-free DNA, and metabolites, which may in turn reveal new therapeutic vulnerabilities. However, many of these approaches are not yet part of the routine clinical management of prostate cancer.

This Special Issue is seeking original research articles, clinical trial reports, and reviews focused on innovative approaches to the development of prostate cancer therapies with novel companion biomarkers to aid in patient stratification.

Prof. Lisa M. Butler
Prof. Lisa G. Horvath
Guest Editors

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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
  • drug development
  • companion biomarkers
  • patient selection

Published Papers (6 papers)

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Research

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18 pages, 1767 KiB  
Article
Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants
by Margaret M. Centenera, Andrew D. Vincent, Max Moldovan, Hui-Ming Lin, David J. Lynn, Lisa G. Horvath and Lisa M. Butler
Cancers 2022, 14(7), 1708; https://doi.org/10.3390/cancers14071708 - 28 Mar 2022
Cited by 5 | Viewed by 2398
Abstract
Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen [...] Read more.
Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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19 pages, 15539 KiB  
Article
Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer
by Hui-Ming Lin, Nicole Yeung, Jordan F. Hastings, David R. Croucher, Kevin Huynh, Thomas G. Meikle, Natalie A. Mellett, Edmond M. Kwan, Ian D. Davis, Ben Tran, Kate L. Mahon, Alison Zhang, Martin R. Stockler, Karen Briscoe, Gavin Marx, Patricia Bastick, Megan L. Crumbaker, Anthony M. Joshua, Arun A. Azad, Peter J. Meikle and Lisa G. Horvathadd Show full author list remove Hide full author list
Cancers 2021, 13(19), 4964; https://doi.org/10.3390/cancers13194964 - 01 Oct 2021
Cited by 13 | Viewed by 2291
Abstract
Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two [...] Read more.
Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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14 pages, 2619 KiB  
Article
A Novel Urine Exosomal lncRNA Assay to Improve the Detection of Prostate Cancer at Initial Biopsy: A Retrospective Multicenter Diagnostic Feasibility Study
by Yun Li, Jin Ji, Ji Lyu, Xin Jin, Xing He, Shaojia Mo, Huan Xu, Jingyi He, Zhi Cao, Xi Chen, Yalong Xu, Lei Wang and Fubo Wang
Cancers 2021, 13(16), 4075; https://doi.org/10.3390/cancers13164075 - 13 Aug 2021
Cited by 20 | Viewed by 2471
Abstract
Purpose: This study aimed at developing and validating a novel noninvasive urinary exosome-based post-DRE (digital rectal examination) lncRNA assay to diagnose PCa (prostate cancer) and clinically significant PCa (Gleason score ≥ 7) from the initial prostate biopsy. Methods: A total of 602 urine [...] Read more.
Purpose: This study aimed at developing and validating a novel noninvasive urinary exosome-based post-DRE (digital rectal examination) lncRNA assay to diagnose PCa (prostate cancer) and clinically significant PCa (Gleason score ≥ 7) from the initial prostate biopsy. Methods: A total of 602 urine samples from eligible participants were collected. The expression levels of urinary exosomal PCA3 (prostate cancer antigen 3) and MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) were detected by qPCR (quantitative real-time PCR). Receiver operating characteristic (ROC) analysis was applied to evaluate the diagnostic performance of PCA3, MALAT1 and the lncRNA assay. A decision curve analysis (DCA) and waterfall plots were used to assess the clinical value of the lncRNA assay. Results: Urinary exosomal PCA3 and MALAT1 were overexpressed in PCa and clinically significant PCa (p < 0.001). The lncRNA assay combining PCA3 and MALAT1 had a better diagnostic performance (AUC 0.828) than the current clinical parameters in detecting PCa. More importantly, the lncRNA assay yielded an AUC of 0.831 to detect clinically significant PCa, which is much higher than that of the current clinical parameters. The lncRNA assay was superior to PSA, f/tPSA and the base model for detecting PCa and clinically significant PCa, with a higher net benefit for almost all threshold probabilities. At the cutoff value of 95% sensitivity, the lncRNA assay could avoid 24.2% unnecessary biopsies while only missing 1.2% of the cases of clinically significant PCa. Conclusion: We developed and validated a novel noninvasive post-DRE urine-based lncRNA assay that presented good diagnostic power and clinical utility for the early diagnosis of PCa and high-grade PCa. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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21 pages, 12925 KiB  
Article
PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1
by Alice Matheux, Matthieu Gassiot, Gaëlle Fromont, Fanny Leenhardt, Abdelhay Boulahtouf, Eric Fabbrizio, Candice Marchive, Aurélie Garcin, Hanane Agherbi, Eve Combès, Alexandre Evrard, Nadine Houédé, Patrick Balaguer, Céline Gongora, Litaty C. Mbatchi and Philippe Pourquier
Cancers 2021, 13(14), 3635; https://doi.org/10.3390/cancers13143635 - 20 Jul 2021
Cited by 9 | Viewed by 2751
Abstract
Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor [...] Read more.
Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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Review

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15 pages, 675 KiB  
Review
Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer
by Ciara S. McNevin, Karen Cadoo, Anne-Marie Baird, Pierre Murchan, Orla Sheils, Ray McDermott and Stephen Finn
Cancers 2021, 13(22), 5697; https://doi.org/10.3390/cancers13225697 - 14 Nov 2021
Cited by 10 | Viewed by 3552
Abstract
Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men [...] Read more.
Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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Other

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12 pages, 593 KiB  
Commentary
Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer
by Maree Pechlivanis, Bethany K. Campbell, Christopher M. Hovens and Niall M. Corcoran
Cancers 2022, 14(1), 166; https://doi.org/10.3390/cancers14010166 - 29 Dec 2021
Viewed by 1608
Abstract
Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely [...] Read more.
Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature. Full article
(This article belongs to the Special Issue Advances in Companion Biomarker Development for Prostate Cancer)
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