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Aberrations of DNA Repair Pathways in Prostate Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 32787

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Special Issue Editors

Prof. Dr. Stergios Boussios

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Guest Editor

1. Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK
2. Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
3. AELIA Organization, 9th Km Thessaloniki–Thermi, 57001 Thessaloniki, Greece
Interests: ovarian cancer; cervical cancer; prostate cancer; colorectal cancer; cancer in pregnancy; homologous recombination of DNA; PARP inhibitors
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Dr. Matin Sheriff

E-Mail Website
Guest Editor

Medway NHS Foundation Trust, Windmill Road, Kent, Gillingham ME7 5NY, UK
Interests: prostate cancer; urology oncology; minimally invasive surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prostate cancer is the second most common neoplasm in men worldwide and the second leading cause of cancer deaths in Western countries. Due to the large-scale sequencing efforts, there is a better understanding of the genomic landscape of prostate cancer. Within this context, recurrent somatic mutations, copy number alterations, and oncogenic structural DNA rearrangements have been identified. These include point mutations in SPOP, FOXA1, and TP53; copy number alterations involving MYC, RB1, PTEN, and CHD1; and E26 transformation-specific (ETS) fusions. Data on mechanisms of DNA repair and experimental evidence still represent an urgent need. The identification of genomic defects in DNA repair has already led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients.

Carriers of BRCA2 pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate. BRCA2 PSVs confer lower overall survival. The association of BRCA1 and prostate cancer has not been replicated in all studies. The National Comprehensive Cancer Network guidelines recommend that BRCA2 carriers should begin PSA screening at 45 years of age, whilst BRCA1 carriers should be advised to consider it. The IMPACT study evaluated a tailored prostate cancer screening in men with BRCA1/2 germline mutation, and proposed annual PSA tests and a prostate biopsy if PSA >3 ng/mL.

In this editorial, we highlight the biology of deleterious inherited or acquired DNA repair pathway aberrations in prostate cancer. The manuscripts should be focused but are not only limited to:

Prostate risk assessment in the era of next-generation sequencing
Prognostic biomarkers in metastatic castration-resistant prostate cancer
Molecular signatures in prostate cancer
Aberrations of DNA repair pathways in prostate cancer
Germline genetic variants in prostate cancer
PARP inhibitors in prostate cancer
Targeting androgen receptor activity in prostate cancer
Resistance to androgen receptor targeting therapies in prostate cancer
Anti-angiogenesis in prostate cancer

Dr. Stergios Boussios
Dr. Matin Sheriff
Guest Editors

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Keywords

prostate cancer
cancer screening
tumor microenvironment
molecular pathogenesis
biomarkers
liquid biopsies
PSA
androgens
androgen receptor
castration resistance
precision medicine

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 205 KiB

Open AccessEditorial

Aberrations of DNA Repair Pathways in Prostate Cancer—The State of the Art

by Stergios Boussios and Matin Sheriff

Int. J. Mol. Sci. 2023, 24(5), 4301; https://doi.org/10.3390/ijms24054301 - 21 Feb 2023

Viewed by 1293

Abstract

Prostate cancer (PC) is the second most commonly diagnosed cancer in males worldwide and the fifth most common cause of cancer-related death in men [...] Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

Research

Jump to: Editorial, Review

17 pages, 2308 KiB

Open AccessArticle

Somatostatin, Cortistatin and Their Receptors Exert Antitumor Actions in Androgen-Independent Prostate Cancer Cells: Critical Role of Endogenous Cortistatin

by Prudencio Sáez-Martínez, Francisco Porcel-Pastrana, Jesús M. Pérez-Gómez, Sergio Pedraza-Arévalo, Enrique Gómez-Gómez, Juan M. Jiménez-Vacas, Manuel D. Gahete and Raúl M. Luque

Int. J. Mol. Sci. 2022, 23(21), 13003; https://doi.org/10.3390/ijms232113003 - 27 Oct 2022

Cited by 4 | Viewed by 2418

Abstract

Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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20 pages, 5928 KiB

Open AccessArticle

Development of VPC-70619, a Small-Molecule N-Myc Inhibitor as a Potential Therapy for Neuroendocrine Prostate Cancer

by Anh-Tien Ton, Jane Foo, Kriti Singh, Joseph Lee, Anastasia Kalyta, Helene Morin, Carl Perez, Fuqiang Ban, Eric Leblanc, Nada Lallous and Artem Cherkasov

Int. J. Mol. Sci. 2022, 23(5), 2588; https://doi.org/10.3390/ijms23052588 - 26 Feb 2022

Cited by 8 | Viewed by 3622

Abstract

The Myc family of transcription factors are involved in the development and progression of numerous cancers, including prostate cancer (PCa). Under the pressure of androgen receptor (AR)-directed therapies resistance can occur, leading to the lethal form of PCa known as neuroendocrine prostate cancer (NEPC), characterized among other features by N-Myc overexpression. There are no clinically approved treatments for NEPC, translating into poor patient prognosis and survival. Therefore, there is a pressing need to develop novel therapeutic avenues to treat NEPC patients. In this study, we investigate the N-Myc-Max DNA binding domain (DBD) as a potential target for small molecule inhibitors and utilize computer-aided drug design (CADD) approaches to discover prospective hits. Through further exploration and optimization, a compound, VPC-70619, was identified with notable anti-N-Myc potency and strong antiproliferative activity against numerous N-Myc expressing cell lines, including those representing NEPC. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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14 pages, 1938 KiB

Open AccessArticle

Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis

by Pai-Chi Teng, Shu-Pin Huang, Chia-Hsin Liu, Ting-Yi Lin, Yi-Chun Cho, Yo-Liang Lai, Shu-Chi Wang, Hsin-Chih Yeh, Chih-Pin Chuu, Deng-Neng Chen, Wei-Chung Cheng and Chia-Yang Li

Int. J. Mol. Sci. 2021, 22(21), 11771; https://doi.org/10.3390/ijms222111771 - 29 Oct 2021

Cited by 7 | Viewed by 2943

Abstract

In the recent decade, the importance of DNA damage repair (DDR) and its clinical application have been firmly recognized in prostate cancer (PC). For example, olaparib was just approved in May 2020 to treat metastatic castration-resistant PC with homologous recombination repair-mutated genes; however, not all patients can benefit from olaparib, and the treatment response depends on patient-specific mutations. This highlights the need to understand the detailed DDR biology further and develop DDR-based biomarkers. In this study, we establish a four-gene panel of which the expression is significantly associated with overall survival (OS) and progression-free survival (PFS) in PC patients from the TCGA-PRAD database. This panel includes DNTT, EXO1, NEIL3, and EME2 genes. Patients with higher expression of the four identified genes have significantly worse OS and PFS. This significance also exists in a multivariate Cox regression model adjusting for age, PSA, TNM stages, and Gleason scores. Moreover, the expression of the four-gene panel is highly correlated with aggressiveness based on well-known PAM50 and PCS subtyping classifiers. Using publicly available databases, we successfully validate the four-gene panel as having the potential to serve as a prognostic and predictive biomarker for PC specifically based on DDR biology. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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Review

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11 pages, 406 KiB

Open AccessReview

Androgen Receptor Gene Pathway Upregulation and Radiation Resistance in Oligometastatic Prostate Cancer

by Helen Saxby, Stergios Boussios and Christos Mikropoulos

Int. J. Mol. Sci. 2022, 23(9), 4786; https://doi.org/10.3390/ijms23094786 - 26 Apr 2022

Cited by 9 | Viewed by 2516

Abstract

Stereotactic ablative body radiotherapy (SABR) is currently used as a salvage intervention for men with oligometastatic prostate cancer (PC), and increasingly so since the results of the Stereotactic Ablative Body Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) trial reported a significant improvement in overall survival with SABR. The addition of androgen deprivation therapy (ADT) to localised prostate radiotherapy improves survival as it sensitises PC to radiotherapy-induced cell death. The importance of the androgen receptor (AR) gene pathway in the development of resistance to radiotherapy is well established. In this review paper, we will examine the data to determine how we can overcome the upregulation of the AR pathway and suggest a strategy for improving outcomes in men with oligometastatic hormone-sensitive PC. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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14 pages, 1994 KiB

Open AccessReview

Novel Insights into Autophagy and Prostate Cancer: A Comprehensive Review

by Davide Loizzo, Savio Domenico Pandolfo, Devin Rogers, Clara Cerrato, Nicola Antonio di Meo, Riccardo Autorino, Vincenzo Mirone, Matteo Ferro, Camillo Porta, Alessandro Stella, Cinzia Bizzoca, Leonardo Vincenti, Marco Spilotros, Monica Rutigliano, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli

Int. J. Mol. Sci. 2022, 23(7), 3826; https://doi.org/10.3390/ijms23073826 - 30 Mar 2022

Cited by 41 | Viewed by 3951

Abstract

Autophagy is a complex process involved in several cell activities, including tissue growth, differentiation, metabolic modulation, and cancer development. In prostate cancer, autophagy has a pivotal role in the regulation of apoptosis and disease progression. Several molecular pathways are involved, including PI3K/AKT/mTOR. However, depending on the cellular context, autophagy may play either a detrimental or a protective role in prostate cancer. For this purpose, current evidence has investigated how autophagy interacts within these complex interactions. In this article, we discuss novel findings about autophagic machinery in order to better understand the therapeutic response and the chemotherapy resistance of prostate cancer. Autophagic-modulation drugs have been employed in clinical trials to regulate autophagy, aiming to improve the response to chemotherapy or to anti-cancer treatments. Furthermore, the genetic signature of autophagy has been found to have a potential means to stratify prostate cancer aggressiveness. Unfortunately, stronger evidence is needed to better understand this field, and the application of these findings in clinical practice still remains poorly feasible. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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21 pages, 1717 KiB

Open AccessReview

BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

by Sidrah Shah, Rachelle Rachmat, Synthia Enyioma, Aruni Ghose, Antonios Revythis and Stergios Boussios

Int. J. Mol. Sci. 2021, 22(23), 12628; https://doi.org/10.3390/ijms222312628 - 23 Nov 2021

Cited by 59 | Viewed by 6065

Abstract

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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20 pages, 1119 KiB

Open AccessReview

Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets

by Evangelia Ioannidou, Michele Moschetta, Sidrah Shah, Jack Steven Parker, Mehmet Akif Ozturk, George Pappas-Gogos, Matin Sheriff, Elie Rassy and Stergios Boussios

Int. J. Mol. Sci. 2021, 22(18), 9926; https://doi.org/10.3390/ijms22189926 - 14 Sep 2021

Cited by 61 | Viewed by 4873

Abstract

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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13 pages, 692 KiB

Open AccessReview

Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

by Aruni Ghose, Michele Moschetta, George Pappas-Gogos, Matin Sheriff and Stergios Boussios

Int. J. Mol. Sci. 2021, 22(18), 9783; https://doi.org/10.3390/ijms22189783 - 10 Sep 2021

Cited by 48 | Viewed by 3746

Abstract

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC. Full article

(This article belongs to the Special Issue Aberrations of DNA Repair Pathways in Prostate Cancer)

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