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Article ; Online: Leveraging homologous recombination repair deficiency in sarcoma.

Slade, Dea / Loizou, Joanna I

2023 Volume 15, Issue 4, Page(s) e17453

Abstract: Personalised oncology is at the forefront of cancer research. The goal of personalised oncology is to selectively kill cancer cells while minimising side effects on normal tissue. This can be achieved by identifying and targeting cancer vulnerabilities ... ...

Abstract	Personalised oncology is at the forefront of cancer research. The goal of personalised oncology is to selectively kill cancer cells while minimising side effects on normal tissue. This can be achieved by identifying and targeting cancer vulnerabilities that distinguish it from normal cells. Many cancers are deficient in high-fidelity DNA repair pathways that maintain genomic stability, such as homologous recombination (HR). Such cancers are highly sensitive to targeted therapies that induce DNA damage or inhibit DNA repair pathways. A notable example and a poster child of personalised oncology are PARP1/2 inhibitors (PARPi) that selectively kill HR-deficient (HRD) cancer cells by preventing repair of DNA gaps or single-strand breaks (SSBs) (Slade, 2020). Inhibitors of cell cycle checkpoints such as CHK1 and WEE1 can also eliminate HRD cancers by pushing cancer cells through the cell cycle despite unrepaired DNA damage and causing death by mitotic catastrophe (Groelly et al, 2022). PARPi have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancer but other cancer types with an HRD signature (HRDness) may also respond to PARPi treatment. Planas-Paz et al (2023) now show that many sarcomas show HRDness and respond to PARP1/2 and WEE1 inhibitors, thus offering a new personalised oncology approach for this treatment-refractory cancer.
MeSH term(s)	Male ; Child ; Humans ; Recombinational DNA Repair ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Homologous Recombination ; DNA Damage ; Sarcoma/genetics ; Sarcoma/drug therapy
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2023-03-17
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202317453
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Article ; Online: Leveraging homologous recombination repair deficiency in sarcoma

Dea Slade / Joanna I Loizou

EMBO Molecular Medicine, Vol 15, Iss 4, Pp n/a-n/a (2023)

2023

Abstract	Personalised oncology is at the forefront of cancer research. The goal of personalised oncology is to selectively kill cancer cells while minimising side effects on normal tissue. This can be achieved by identifying and targeting cancer vulnerabilities that distinguish it from normal cells. Many cancers are deficient in high‐fidelity DNA repair pathways that maintain genomic stability, such as homologous recombination (HR). Such cancers are highly sensitive to targeted therapies that induce DNA damage or inhibit DNA repair pathways. A notable example and a poster child of personalised oncology are PARP1/2 inhibitors (PARPi) that selectively kill HR‐deficient (HRD) cancer cells by preventing repair of DNA gaps or single‐strand breaks (SSBs) (Slade, 2020). Inhibitors of cell cycle checkpoints such as CHK1 and WEE1 can also eliminate HRD cancers by pushing cancer cells through the cell cycle despite unrepaired DNA damage and causing death by mitotic catastrophe (Groelly et al, 2022). PARPi have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancer but other cancer types with an HRD signature (HRDness) may also respond to PARPi treatment. Planas‐Paz et al (2023) now show that many sarcomas show HRDness and respond to PARP1/2 and WEE1 inhibitors, thus offering a new personalised oncology approach for this treatment‐refractory cancer.
Keywords	Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR-based screens.

Wilson, Jordan / Loizou, Joanna I

Molecular oncology

2022 Volume 16, Issue 21, Page(s) 3778–3791

Abstract: The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage response for the treatment of cancer. Historically, interactions between two genes have had a ... ...

Abstract	The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage response for the treatment of cancer. Historically, interactions between two genes have had a longstanding presence in genetics and have been identified through forward genetic screens that rely on the molecular basis of the characterized phenotypes, typically caused by mutations in single genes. While such complex genetic interactions between genes have been studied extensively in model organisms, they have only recently been prioritized as therapeutic strategies due to technological advancements in genetic screens. Here, we discuss synthetic lethal and viable interactions within the DNA damage response and present how CRISPR-based genetic screens and chemical compounds have allowed for the systematic identification and targeting of such interactions for the treatment of cancer.
MeSH term(s)	Humans ; CRISPR-Cas Systems ; Neoplasms/genetics ; Mutation ; Genetic Testing ; DNA Damage
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13272
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Article: Interplay between Cellular Metabolism and the DNA Damage Response in Cancer.

Moretton, Amandine / Loizou, Joanna I

Cancers

2020 Volume 12, Issue 8

Abstract: Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved ... ...

Abstract	Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.
Language	English
Publishing date	2020-07-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12082051
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Article ; Online: Decomposing the mutational landscape of cancer genomes with RepairSig.

Bernardo, Sara / Meyenberg, Mathilde / Loizou, Joanna I

Cell systems

2021 Volume 12, Issue 10, Page(s) 953–955

Abstract: Mutational signatures are the outcomes of mutagenic processes that occur prior to, and during, tumorigenesis as a result of DNA damage, DNA repair, and DNA replication. In this issue of Cell Systems, Wojtowicz et al. introduce a new computational model ... ...

Abstract	Mutational signatures are the outcomes of mutagenic processes that occur prior to, and during, tumorigenesis as a result of DNA damage, DNA repair, and DNA replication. In this issue of Cell Systems, Wojtowicz et al. introduce a new computational model aimed at deconstructing the mutational processes that shape cancer genomes.
MeSH term(s)	DNA Damage/genetics ; DNA Repair/genetics ; Genome, Human/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics
Language	English
Publishing date	2021-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2021.09.009
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Article: Tissue specificity of DNA repair: the CRISPR compass.

Ferreira da Silva, Joana / Meyenberg, Mathilde / Loizou, Joanna I

Trends in genetics : TIG

2021 Volume 37, Issue 11, Page(s) 958–962

Abstract: CRISPR-Cas9-mediated genome editing holds great promise for the correction of pathogenic variants in humans. However, its therapeutic implementation is hampered due to unwanted editing outcomes. A better understanding of cell type- and tissue-specific ... ...

Abstract	CRISPR-Cas9-mediated genome editing holds great promise for the correction of pathogenic variants in humans. However, its therapeutic implementation is hampered due to unwanted editing outcomes. A better understanding of cell type- and tissue-specific DNA repair processes will ultimately enable precise control of editing outcomes for safer and effective therapies.
MeSH term(s)	CRISPR-Cas Systems/genetics ; DNA Repair/genetics ; Gene Editing ; Humans ; Organ Specificity/genetics
Language	English
Publishing date	2021-08-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2021.07.010
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Article: Tissue Specific DNA Repair Outcomes Shape the Landscape of Genome Editing.

Meyenberg, Mathilde / Ferreira da Silva, Joana / Loizou, Joanna I

Frontiers in genetics

2021 Volume 12, Page(s) 728520

Abstract: The use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has moved from bench to bedside in less than 10years, realising the vision of correcting disease through genome editing. The accuracy and safety of this approach relies on ...

Abstract	The use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has moved from bench to bedside in less than 10years, realising the vision of correcting disease through genome editing. The accuracy and safety of this approach relies on the precise control of DNA damage and repair processes to achieve the desired editing outcomes. Strategies for modulating pathway choice for repairing CRISPR-mediated DNA double-strand breaks (DSBs) have advanced the genome editing field. However, the promise of correcting genetic diseases with CRISPR-Cas9 based therapies is restrained by a lack of insight into controlling desired editing outcomes in cells of different tissue origin. Here, we review recent developments and urge for a greater understanding of tissue specific DNA repair processes of CRISPR-induced DNA breaks. We propose that integrated mapping of tissue specific DNA repair processes will fundamentally empower the implementation of precise and safe genome editing therapies for a larger variety of diseases.
Language	English
Publishing date	2021-09-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.728520
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Article ; Online: Targeting the DNA Repair Enzyme Polymerase θ in Cancer Therapy.

Schrempf, Anna / Slyskova, Jana / Loizou, Joanna I

Trends in cancer

2020 Volume 7, Issue 2, Page(s) 98–111

Abstract: Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA double-strand break (DSB) ... ...

Abstract	Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA double-strand break (DSB) repair, is often upregulated in cancer. POLQ is synthetic lethal with various DNA repair genes, including known cancer drivers such as BRCA1/2, making it essential in homologous recombination-deficient cancers. Thus, POLQ represents a promising target in cancer therapy and efforts for the development of POLQ inhibitors are actively underway with first clinical trials due to start in 2021. This review summarizes the journey of POLQ from a backup DNA repair enzyme to a promising therapeutic target for cancer treatment.
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; DNA Repair/drug effects ; DNA-Directed DNA Polymerase/metabolism ; Disease Models, Animal ; Drug Development/trends ; Homologous Recombination/drug effects ; Humans ; Mice ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/mortality ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Nucleic Acid Synthesis Inhibitors/therapeutic use ; Prognosis ; Synthetic Lethal Mutations/drug effects ; DNA Polymerase theta
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Nucleic Acid Synthesis Inhibitors ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2020-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2020.09.007
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Article ; Online: Synthetic Lethal Interactions for Kinase Deficiencies to DNA Damage Chemotherapeutics.

Robinson-Garcia, Lydia / Ferreira da Silva, Joana / Loizou, Joanna I

Cancer research

2019 Volume 79, Issue 22, Page(s) 5693–5698

Abstract: Kinases are signaling enzymes that regulate diverse cellular processes. As such, they are frequently mutated in cancer and therefore represent important targets for drug discovery. However, until recently, systematic approaches to identify ... ...

Abstract	Kinases are signaling enzymes that regulate diverse cellular processes. As such, they are frequently mutated in cancer and therefore represent important targets for drug discovery. However, until recently, systematic approaches to identify vulnerabilities and resistances of kinases to DNA-damaging chemotherapeutics have not been possible, partially due to the lack of appropriate technologies. With the advent of CRISPR-Cas9, a comprehensive study has investigated the cellular survival of more than 300 kinase-deficient isogenic cell lines to a diverse panel of DNA-damaging agents, enriched for chemotherapeutics. Here, we discuss how this approach has allowed for the rational development of combination therapies that are aimed at using synthetic lethal interactions between kinase deficiencies and DNA-damaging agents that are used as chemotherapeutics.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Cell Survival/drug effects ; Clustered Regularly Interspaced Short Palindromic Repeats/drug effects ; DNA Damage/drug effects ; Drug Discovery/methods ; Humans ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Phosphotransferases/metabolism
Chemical Substances	Antineoplastic Agents ; Phosphotransferases (EC 2.7.-)
Language	English
Publishing date	2019-08-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-19-1364
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Article ; Online: Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease.

Prochazkova, Jana / Loizou, Joanna I

Immunology

2015 Volume 147, Issue 1, Page(s) 11–20

Abstract: In recent years, several novel congenital human disorders have been described with defects in lymphoid B-cell and T-cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include ... ...

Abstract	In recent years, several novel congenital human disorders have been described with defects in lymphoid B-cell and T-cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double-strand break repair, as well as compromised DNA damage-induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B-cell and T-cell development, as well as human diseases that arise through defects in these pathways.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/immunology ; Cell Transformation, Neoplastic/pathology ; DNA Damage/genetics ; DNA Repair/genetics ; DNA Repair-Deficiency Disorders/genetics ; DNA Repair-Deficiency Disorders/immunology ; DNA Repair-Deficiency Disorders/pathology ; Genetic Predisposition to Disease ; Humans ; Mutation ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Phenotype ; Recombination, Genetic ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology
Language	English
Publishing date	2015-11-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.12547
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