Special Issue "DNA Repair Pathways in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Eddy S. Yang

Department of Radiation Oncology, University of Alabama-Birmingham, 1720 2nd Ave South, Birmingham, AL 35294, USA
Website | E-Mail
Phone: +1-205-996-0780
Interests: PARP, DNA repair, BRCA1, BRCA2, EGFR, synthetic lethality, experimental therapeutics, breast cancer, ovarian cancer, prostate cancer, head and neck cancer

Special Issue Information

Dear Colleagues,

Genomic instability and DNA repair defects are a hallmark of cancer that is more prevalent than previously thought. Recent data from genetic studies, most notably from The Cancer Genome Atlas (TCGA) projects, have shown many tumor types to harbor genetic and epigenetic alterations in DNA repair pathways. These data have made the targeting of DNA repair proteins for cancer therapy increasingly attractive, especially given the recent successes of the PARP inhibitors. Furthermore, as resistance to therapy remains a clinical challenge, combinations of targeted therapies are needed. Moreover, the DNA damage response has crosstalk with inflammation and immune pathways. This and the fact that genomic instability can increase mutational burden and increase neoantigen presentation points to potential synergies between compounds targeting DNA repair and immune therapies. This Special Issue of Cancers will review the role of DNA repair pathways in cancer biology, inflammation, and the immune system and highlight novel targets currently in clinical testing. Research articles on these topics are also welcome.

Dr. Eddy S. Yang
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 papers will be 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 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 1800 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.

Published Papers (9 papers)

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Editorial

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Open AccessEditorial The Impact of DNA Repair Pathways in Cancer Biology and Therapy
Received: 14 September 2017 / Revised: 15 September 2017 / Accepted: 18 September 2017 / Published: 19 September 2017
Cited by 1 | PDF Full-text (164 KB) | HTML Full-text | XML Full-text
Abstract
Genomic instability is one of the key hallmarks of cancer progression [1].[...] Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)

Research

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Open AccessArticle Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach
Received: 15 March 2017 / Revised: 1 June 2017 / Accepted: 2 June 2017 / Published: 6 June 2017
Cited by 5 | PDF Full-text (5324 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals [...] Read more.
The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a ‘plant radiation biodosimeter’, that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana—based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Review

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Open AccessReview Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors
Received: 16 July 2017 / Revised: 18 August 2017 / Accepted: 18 August 2017 / Published: 22 August 2017
Cited by 6 | PDF Full-text (577 KB) | HTML Full-text | XML Full-text
Abstract
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors [...] Read more.
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer
Received: 19 June 2017 / Revised: 30 June 2017 / Accepted: 3 July 2017 / Published: 6 July 2017
Cited by 5 | PDF Full-text (897 KB) | HTML Full-text | XML Full-text
Abstract
DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect [...] Read more.
DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair
Received: 8 April 2017 / Revised: 21 May 2017 / Accepted: 6 June 2017 / Published: 9 June 2017
Cited by 13 | PDF Full-text (2112 KB) | HTML Full-text | XML Full-text
Abstract
Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions [...] Read more.
Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep-seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma
Received: 10 March 2017 / Revised: 10 May 2017 / Accepted: 22 May 2017 / Published: 26 May 2017
Cited by 6 | PDF Full-text (2344 KB) | HTML Full-text | XML Full-text
Abstract
Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize [...] Read more.
Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview MTH1 as a Chemotherapeutic Target: The Elephant in the Room
Received: 25 March 2017 / Revised: 29 April 2017 / Accepted: 29 April 2017 / Published: 8 May 2017
Cited by 10 | PDF Full-text (1030 KB) | HTML Full-text | XML Full-text
Abstract
Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated [...] Read more.
Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview Targeting the ATR-CHK1 Axis in Cancer Therapy
Received: 15 February 2017 / Revised: 23 April 2017 / Accepted: 25 April 2017 / Published: 27 April 2017
Cited by 22 | PDF Full-text (3036 KB) | HTML Full-text | XML Full-text
Abstract
Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article [...] Read more.
Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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Open AccessReview DNA Repair Pathway Alterations in Bladder Cancer
Received: 7 March 2017 / Revised: 22 March 2017 / Accepted: 23 March 2017 / Published: 27 March 2017
Cited by 6 | PDF Full-text (457 KB) | HTML Full-text | XML Full-text
Abstract
Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may [...] Read more.
Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy. Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
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