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Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 29215

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Special Issue Editor

Dr. Pierre-Marie Girard

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Guest Editor

Institut Curie, Centre de Recherche, Université Paris-Saclay, Bâtiment 112, Unité de recherche U1021-UMR3347, Rue Henry Becquerel, CS 90030, 91401 ORSAY cedex, France
Interests: cancer treatment; innovative therapies; radiotherapy; chemotherapy; cold pressure plasma therapy; DNA repair; DNA damage; cell cycle; ROS

Special Issue Information

Dear Colleagues,

50 years ago, Goodman and Gilman, in Pharmacologic Basis of Therapeutics (1970), described the relationship between desired and undesired effects of therapy as the therapeutic index (TI), which is defined as the margin of safety that exists between the dose that produces the desired effect and the dose that produces unwanted and possibly dangerous side-effects. Improving the relationship between desired and undesired effects of therapy is a major goal of cancer therapy. A major challenge in the development of cancer therapeutics is the identification of biological targets and pathways, and the subsequent design of molecules to fight cancer cells. All cancers display defects in DNA repair, and the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. These observations have paved the way to the development of numerous DNA repair inhibitors that will increase sensitivity to traditional chemotherapeutics. Additionally, synthetic lethal approaches to cancer therapy have provided novel mechanisms to specifically target cancer cells while sparing non-cancer cells and thereby reducing toxicity associated with treatment.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on all aspects of the development of DNA repair inhibitors, with a special focus on the improvement of the therapeutic index.

Dr. Pierre-Marie Girard
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 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

therapeutic index
DNA repair inhibitor
DNA damage repair
combination therapy
cancer therapy
healthy tissue
tumor
cell survival
cell death
model systems
drug discovery
clinical trial

Published Papers (6 papers)

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Research

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15 pages, 4397 KiB

Open AccessArticle

Targeting CX3CR1 Suppresses the Fanconi Anemia DNA Repair Pathway and Synergizes with Platinum

by Jemina Lehto, Anna Huguet Ninou, Dimitrios Chioureas, Jos Jonkers and Nina M. S. Gustafsson

Cancers 2021, 13(6), 1442; https://doi.org/10.3390/cancers13061442 - 22 Mar 2021

Cited by 5 | Viewed by 6766

Abstract

The C-X3-C motif chemokine receptor 1 (CX3CR1, fractalkine receptor) is associated with neoplastic transformation, inflammation, neurodegenerative diseases and aging, and the small molecule inhibitor KAND567 targeting CX3CR1 (CX3CR1i) is evaluated in clinical trials for acute systemic inflammation upon SARS-CoV-2 infections. Here we identify a hitherto unknown role of CX3CR1 in Fanconi anemia (FA) pathway mediated repair of DNA interstrand crosslinks (ICLs) in replicating cells. FA pathway activation triggers CX3CR1 nuclear localization which facilitates assembly of the key FA protein FANCD2 into foci. Interfering with CX3CR1 function upon ICL-induction results in inability of replicating cells to progress from S phase, replication fork stalling and impaired chromatin recruitment of key FA pathway factors. Consistent with defective FA repair, CX3CR1i results in increased levels of residual cisplatin-DNA adducts and decreased cell survival. Importantly, CX3CR1i synergizes with platinum agents in a nonreversible manner in proliferation assays including platinum resistant models. Taken together, our results reveal an unanticipated interplay between CX3CR1 and the FA pathway and show for the first time that a clinical-phase small molecule inhibitor targeting CX3CR1 might show benefit in improving responses to DNA crosslinking chemotherapeutics. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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Review

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23 pages, 3679 KiB

Open AccessReview

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

by Ukhyun Jo, Yasuhisa Murai, Naoko Takebe, Anish Thomas and Yves Pommier

Cancers 2021, 13(18), 4601; https://doi.org/10.3390/cancers13184601 - 14 Sep 2021

Cited by 19 | Viewed by 3900

Abstract

Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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17 pages, 1100 KiB

Open AccessReview

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

by Camille Franchet, Jean-Sébastien Hoffmann and Florence Dalenc

Cancers 2021, 13(16), 4132; https://doi.org/10.3390/cancers13164132 - 17 Aug 2021

Cited by 5 | Viewed by 2467

Abstract

As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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37 pages, 1413 KiB

Open AccessReview

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

by Paula Pellenz Tomasini, Temenouga Nikolova Guecheva, Natalia Motta Leguisamo, Sarah Péricart, Anne-Cécile Brunac, Jean Sébastien Hoffmann and Jenifer Saffi

Cancers 2021, 13(13), 3130; https://doi.org/10.3390/cancers13133130 - 23 Jun 2021

Cited by 14 | Viewed by 4365

Abstract

Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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20 pages, 2474 KiB

Open AccessReview

Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

by Esin Orhan, Carolina Velazquez, Imene Tabet, Claude Sardet and Charles Theillet

Cancers 2021, 13(12), 2930; https://doi.org/10.3390/cancers13122930 - 11 Jun 2021

Cited by 21 | Viewed by 7930

Abstract

The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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14 pages, 1604 KiB

Open AccessReview

Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

by Danielle P. Johnson, Mahesh B. Chandrasekharan, Marie Dutreix and Srividya Bhaskara

Cancers 2021, 13(3), 381; https://doi.org/10.3390/cancers13030381 - 20 Jan 2021

Cited by 4 | Viewed by 2798

Abstract

Aberrant DNA repair pathways that underlie developmental diseases and cancers are potential targets for therapeutic intervention. Targeting DNA repair signal effectors, modulators and checkpoint proteins, and utilizing the synthetic lethality phenomena has led to seminal discoveries. Efforts to efficiently translate the basic findings to the clinic are currently underway. Chromatin modulation is an integral part of DNA repair cascades and an emerging field of investigation. Here, we discuss some of the key advancements made in DNA repair-based therapeutics and what is known regarding crosstalk between chromatin and repair pathways during various cellular processes, with an emphasis on cancer. Full article

(This article belongs to the Special Issue Recent Advances in the Improvement of the Therapeutic Index of DNA Repair Inhibitors in Standalone or in Combination Therapy)

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