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Novel Insights into the Molecular Mechanisms of Treatment Resistance and Predictive Biomarkers in Metastatic Prostate Cancer

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 13020

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Special Issue Editors

Dr. Albert Font

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Guest Editor

Badalona–Badalona Applied Research Group in Oncology (B·ARGO), Catalan Institute of Oncology, 08916 Badalona, Spain
Interests: genitourinary tumors
Special Issues, Collections and Topics in MDPI journals

Dr. Vicenç Ruiz de Porras

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Guest Editor

1. Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
2. Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
Interests: metastatic prostate cancer; bladder cancer; therapy resistance; chemotherapy; predictive biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prostate cancer (PC) is the most common malignancy in men and a major cause of cancer death. For patients with PC who experience disease relapse after local therapy or for those with metastatic disease, androgen deprivation therapy (ADT) is the backbone of systemic therapy. However, despite significant initial responses to ADT, almost all metastatic patients progress to an incurable metastatic castration-resistant prostate cancer (mCRPC), defined as radiographic progression and/or a rise in prostate-specific antigen (PSA) despite having a castrate level of testosterone. Although several new options for the treatment of mCRPC have been approved in the last decade—the CYP17 inhibitor abiraterone, the androgen receptor antagonist enzalutamide, the taxane cabazitaxel, the immunotherapy sipuleucel-T, the alpha-emmitter radium-223 as well as PARP inhibitors and PSMA radioligands—unfortunately, not all patients initially respond to these therapies, while nearly all of them develop resistance. Thus, understanding the molecular and clinical mechanisms leading to therapy resistance and determine new predictive biomarkers is crucial to achieving further advances in the sequencing of available drugs and targeting new therapeutic pathways that improve the clinical management of metastatic prostate cancer patients in order to pursue a personalized treatment approach. This Special Issue of Cancers, therefore, encompasses original and review articles on the molecular and clinical mechanisms leading to tumour resistance to current treatment options, new therapeutic strategies to overcome such resistance, and new biomarkers predicting response to therapies for metastatic prostate cancer.

Dr. Albert Font Pous
Dr. Vicenç Ruiz de Porras
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

metastatic prostate cancer
therapy resistance
predictive biomarkers
chemotherapy
hormonal therapy
androgen deprivation therapy
PARP inhibitors

Published Papers (4 papers)

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Research

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17 pages, 1728 KiB

Open AccessArticle

HSP27/Menin Expression as New Prognostic Serum Biomarkers of Prostate Cancer Aggressiveness Independent of PSA

by Asma Bourefis, Hajira Berredjem, Omar Djeffal, Thi Khanh Le, Sophie Giusiano and Palma Rocchi

Cancers 2022, 14(19), 4773; https://doi.org/10.3390/cancers14194773 - 29 Sep 2022

Cited by 2 | Viewed by 1969

Abstract

The screening of PCa is based on two tests, the total PSA test and the rectal examination. However, PSA is not specific for PCa stage confirmation, leading in false positive result and involving PCa over-diagnosis and over-treatment. HSP27 and Menin have been found to be overexpressed in a wide range of human cancers. Recent studies showed how HSP27 interacts with and stabilizes Menin to lead PCa progression and treatment resistance. The purpose of our study was to evaluate the correlation of HSP27 and Menin molecular expression, and their prognosis value in PCa with respect to clinicopathological features. Elisa was employed to measure serum HSP27 and Menin concentrations in 73 PCa patients and 80 healthy individuals. Immunohistochemistry (IHC) was used to determine HSP27 and Menin tissue expression in 57 tumors and 4 Benign Prostatic Hyperplasia (BPH) tissues. Serum HSP27 expression correlated with its tissue expression in all PCa patients, whereas serum Menin expression correlated only with tissue expression in aggressive PCa patients. Moreover, the results showed a positive correlation between HSP27 and Menin either in serum (r = 0.269; p = 0.021) or in tissue (r = 0.561; p < 0.0001). In aggressive PCa, serum expression of HSP27 and Menin was positively correlated (r = 0.664; R = 0.441; p = 0.001). The correlation between HSP27 and Menin expression in tissue was found only in patients with aggressive PCa (r = 0.606; R = 0.367; p = 0.004). Statistical analysis showed that the expression of both biomarkers was positively correlated with the hormone resistance or sensitivity, tumor aggressiveness, metastasis, Gleason Score, death and did not significantly correlate with age and PSA. Survival was illustrated by Kaplan–Meier curves; increased HSP27 and Menin expression correlated with shorter survival of PCa patients (p = 0.001 and p < 0.0001, respectively). Accuracy in predicting aggressiveness was quantified by the Area Under the Curve (AUC) of Receiver Operating Characteristic (ROC). We demonstrated that the combination of HSP27/Menin was statistically greater than PSA; it achieved an AUC of 0.824 (95% CI, 0.730–0.918; p < 0.0001). However, HSP27/Menin/PSA combination decreased the diagnostic value with an AUC of 0.569 (95% CI, 0.428–0.710; p = 0.645). Our work suggests the potential role of HSP27/Menin as diagnostic and prognostic biomarkers. Full article

(This article belongs to the Special Issue Novel Insights into the Molecular Mechanisms of Treatment Resistance and Predictive Biomarkers in Metastatic Prostate Cancer)

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17 pages, 7269 KiB

Open AccessArticle

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

by Natalia Jiménez, Òscar Reig, Mercedes Marín-Aguilera, Caterina Aversa, Laura Ferrer-Mileo, Albert Font, Alejo Rodriguez-Vida, Miguel Ángel Climent, Sara Cros, Isabel Chirivella, Montserrat Domenech, Mariona Figols, Enrique González-Billalabeitia, Daniel Jiménez Peralta, Leonardo Rodríguez-Carunchio, Samuel García-Esteve, Marta Garcia de Herreros, Maria J. Ribal, Aleix Prat and Begoña Mellado

Cancers 2022, 14(19), 4757; https://doi.org/10.3390/cancers14194757 - 29 Sep 2022

Cited by 3 | Viewed by 1916

Abstract

(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3–0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4–0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2–0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1–3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1–2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2–2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2–1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1–3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX. Full article

(This article belongs to the Special Issue Novel Insights into the Molecular Mechanisms of Treatment Resistance and Predictive Biomarkers in Metastatic Prostate Cancer)

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27 pages, 4761 KiB

Open AccessArticle

Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

by Javier Octavio Mejía-Hernández, Dinesh Raghu, Franco Caramia, Nicholas Clemons, Kenji Fujihara, Thomas Riseborough, Amina Teunisse, Aart G. Jochemsen, Lars Abrahmsén, Giovanni Blandino, Andrea Russo, Cristina Gamell, Stephen B. Fox, Catherine Mitchell, Elena A. Takano, David Byrne, Panimaya Jeffreena Miranda, Reem Saleh, Heather Thorne, Shahneen Sandhu, Scott G. Williams, Simon P. Keam, Ygal Haupt and Sue Haupt Show full author list Hide full author list

Cancers 2022, 14(16), 3947; https://doi.org/10.3390/cancers14163947 - 16 Aug 2022

Cited by 4 | Viewed by 2678

Abstract

Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death. Full article

(This article belongs to the Special Issue Novel Insights into the Molecular Mechanisms of Treatment Resistance and Predictive Biomarkers in Metastatic Prostate Cancer)

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17 pages, 2220 KiB

Open AccessPerspective

Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer

by Nicola J. Nasser

Cancers 2022, 14(8), 1959; https://doi.org/10.3390/cancers14081959 - 13 Apr 2022

Cited by 3 | Viewed by 5596

Abstract

Treatment of metastatic prostate cancer was historically performed via bilateral orchiectomy to achieve castration. An alternative to surgical castration is the administration of subcutaneous recombinant luteinizing hormone-releasing hormone (LHRH). LHRH causes the pituitary gland to produce luteinizing hormone (LH), which results in synthesis and secretion of testosterone from the testicles. When LHRH levels are continuously high, the pituitary gland stops producing LH, which results in reduced testosterone production by the testicles. Long-acting formulations of LHRH were developed, and its use replaced surgical orchiectomy in the vast majority of patients. Combining LHRH and radiation therapy was shown to increase survival of prostate cancer patients with locally advanced disease. Here, we present a hypothesis, and preliminary evidence based on previous randomized controlled trials, that androgen surge during radiation, rather than its suppression, could be responsible for the enhanced prostate cancer cell kill during radiation. Starting LHRH agonist on the first day of radiation therapy, as in the EORTC 22863 study, should be the standard of care when treating locally advanced prostate cancer. We are developing formulations of short-acting LHRH agonists that induce androgen flare, without subsequent androgen deprivation, which could open the door for an era in which locally advanced prostate cancer could be cured while patients maintain potency. Full article

(This article belongs to the Special Issue Novel Insights into the Molecular Mechanisms of Treatment Resistance and Predictive Biomarkers in Metastatic Prostate Cancer)

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