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Article: Exploiting Cancer Synthetic Lethality in Cancer-Lessons Learnt from PARP Inhibitors.

Pettitt, Stephen J / Ryan, Colm J / Lord, Christopher J

2023 Volume 186, Page(s) 13–23

Abstract: PARP inhibitors now have proven utility in the treatment of homologous recombination (HR) defective cancers. These drugs, and the synthetic lethality effect they exploit, have not only taught us how to approach the treatment of HR defective cancers but ... ...

Abstract	PARP inhibitors now have proven utility in the treatment of homologous recombination (HR) defective cancers. These drugs, and the synthetic lethality effect they exploit, have not only taught us how to approach the treatment of HR defective cancers but have also illuminated how resistance to a synthetic lethal approach can occur, how cancer-associated synthetic lethal effects are perhaps more complex than we imagine, how the better use of biomarkers could improve the success of treatment and even how drug resistance might be targeted. Here, we discuss some of the lessons learnt from the study of PARP inhibitor synthetic lethality and how these lessons might have wider application. Specifically, we discuss the concept of synthetic lethal penetrance, phenocopy effects in cancer such as BRCAness, synthetic lethal resistance, the polygenic and complex nature of synthetic lethal interactions, how evolutionary double binds could be exploited in treatment as well as future horizons for the field.
MeSH term(s)	Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Synthetic Lethal Mutations ; Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ISSN	0927-3042
ISSN	0927-3042
DOI	10.1007/978-3-031-30065-3_2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Communicating beyond the information given can make the communicator's attitudes toward a social group more extreme.

Decker, Kaleigh A / Lord, Charles G / Holland, Christopher J

The Journal of social psychology

2022 , Page(s) 1–18

Abstract: Three experiments tested how communicating attributes of initially liked or disliked groups might create more extreme attitudes. We gave non-neutral participants information about previously unknown groups and asked them to write social media posts ... ...

Abstract	Three experiments tested how communicating attributes of initially liked or disliked groups might create more extreme attitudes. We gave non-neutral participants information about previously unknown groups and asked them to write social media posts describing the group to others. Participants who wrote social media posts to friends (Experiment 1,
Language	English
Publishing date	2022-10-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2066653-6
ISSN	1940-1183 ; 0022-4545
ISSN (online)	1940-1183
ISSN	0022-4545
DOI	10.1080/00224545.2022.2133678
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Article ; Online: Complex synthetic lethality in cancer.

Ryan, Colm J / Devakumar, Lovely Paul Solomon / Pettitt, Stephen J / Lord, Christopher J

Nature genetics

2023 Volume 55, Issue 12, Page(s) 2039–2048

Abstract: The concept of synthetic lethality has been widely applied to identify therapeutic targets in cancer, with varying degrees of success. The standard approach normally involves identifying genetic interactions between two genes, a driver and a target. In ... ...

Abstract	The concept of synthetic lethality has been widely applied to identify therapeutic targets in cancer, with varying degrees of success. The standard approach normally involves identifying genetic interactions between two genes, a driver and a target. In reality, however, most cancer synthetic lethal effects are likely complex and also polygenic, being influenced by the environment in addition to involving contributions from multiple genes. By acknowledging and delineating this complexity, we describe in this article how the success rate in cancer drug discovery and development could be improved.
MeSH term(s)	Humans ; Synthetic Lethal Mutations/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Discovery
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01557-x
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Systemic Therapy for Hereditary Breast Cancers.

Harvey-Jones, Elizabeth J / Lord, Christopher J / Tutt, Andrew N J

Hematology/oncology clinics of North America

2022 Volume 37, Issue 1, Page(s) 203–224

Abstract: Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including ...

Abstract	Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including approved chemotherapeutic approaches and also targeted treatment approaches using poly-(ADP ribose) polymerase inhibitors. We also discuss experimental approaches to treating hereditary breast cancer, including new small molecule DNA repair inhibitors and also immunomodulatory agents. Finally, we discuss how drug resistance emerges in patients with hereditary breast cancer, how this might be delayed or prevented, and how biomarker-adapted treatment is molding the future management of hereditary breast cancer.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Genes, BRCA2 ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; DNA Repair
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	93115-9
ISSN	1558-1977 ; 0889-8588
ISSN (online)	1558-1977
ISSN	0889-8588
DOI	10.1016/j.hoc.2022.08.018
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Article ; Online: Resistance to DNA repair inhibitors in cancer.

Baxter, Joseph S / Zatreanu, Diana / Pettitt, Stephen J / Lord, Christopher J

Molecular oncology

2022 Volume 16, Issue 21, Page(s) 3811–3827

Abstract: The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults ... ...

Abstract	The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polθ (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.
MeSH term(s)	Humans ; DNA Repair ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Neoplasms/genetics ; DNA Damage ; Mutation
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2022-06-05
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13224
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Article ; Online: Global prevalence of hospital admissions for low back pain: a systematic review with meta-analysis.

Melman, Alla / Lord, Harrison J / Coombs, Danielle / Zadro, Joshua / Maher, Christopher G / Machado, Gustavo C

BMJ open

2023 Volume 13, Issue 4, Page(s) e069517

Abstract: Objectives: To determine the proportion of low back pain presentations that are admitted to hospital from the emergency department (ED), the proportion of hospital admissions due to a primary diagnosis of low back pain and the mean hospital length of ... ...

Abstract	Objectives: To determine the proportion of low back pain presentations that are admitted to hospital from the emergency department (ED), the proportion of hospital admissions due to a primary diagnosis of low back pain and the mean hospital length of stay (LOS), globally. Methods: We searched MEDLINE, CINAHL, EMBASE, Web of Science, PsycINFO and LILACS from inception to July 2022. Secondary data were retrieved from publicly available government agency publications and international databases. Studies investigating admitted patients aged >18 years with a primary diagnosis of musculoskeletal low back pain and/or lumbosacral radicular pain were included. Results: There was high heterogeneity in admission rates for low back pain from the ED, with a median of 9.6% (IQR 3.3-25.2; 9 countries). The median percentage of all hospital admissions that were due to low back pain was 0.9% (IQR 0.6-1.5; 30 countries). The median hospital LOS across 39 countries was 6.2 days for 'dorsalgia' (IQR 4.4-8.6) and 5.4 days for 'intervertebral disc disorders' (IQR 4.1-8.4). Low back pain admissions per 100 000 population had a median of 159.1 (IQR 82.6-313.8). The overall quality of the evidence was moderate. Conclusion: This is the first systematic review with meta-analysis summarising the global prevalence of hospital admissions and hospital LOS for low back pain. There was relatively sparse data from rural and regional regions and low-income countries, as well as high heterogeneity in the results.
MeSH term(s)	Humans ; Low Back Pain/epidemiology ; Low Back Pain/therapy ; Prevalence ; Hospitalization ; Length of Stay ; Back Pain ; Emergency Service, Hospital ; Hospitals
Language	English
Publishing date	2023-04-21
Publishing country	England
Document type	Meta-Analysis ; Systematic Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2022-069517
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Article ; Online: PARP Inhibitors - Trapped in a Toxic Love Affair.

Krastev, Dragomir B / Wicks, Andrew J / Lord, Christopher J

Cancer research

2021 Volume 81, Issue 22, Page(s) 5605–5607

Abstract: It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination-defective cancers. In 2012, ... ...

Abstract	It is often the case that when an investigational cancer drug first enters clinical development, its precise mechanism of action is unclear. This was the case for PARP inhibitors (PARPi) used to treat homologous recombination-defective cancers. In 2012, nearly a decade after the first PARPi entered clinical development, work from Murai and colleagues demonstrated that clinical PARPi not only inhibit the catalytic activity of PARP1, PARylation, but also "trap" PARP1 on DNA; this latter effect being responsible for much of the tumor cell cytotoxicity caused by these drugs. We discuss how this work not only changed our understanding about how PARPi work, but also stimulated subsequent dissection of how PARP1 carries out its normal function in the absence of inhibitor.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Homologous Recombination ; Humans ; Love ; Neoplasms/drug therapy ; Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
Chemical Substances	Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-21-3201
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Article ; Online: First-line PARP inhibition in ovarian cancer - standard of care for all?

Banerjee, Susana N / Lord, Christopher J

Nature reviews. Clinical oncology

2019 Volume 17, Issue 3, Page(s) 136–137

MeSH term(s)	Antineoplastic Agents/therapeutic use ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Clinical Trials as Topic ; Female ; Humans ; Mutation ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Progression-Free Survival ; Standard of Care
Chemical Substances	Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2019-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-020-0335-9
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Zs.A 6029: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dissecting PARP inhibitor resistance with functional genomics.

Pettitt, Stephen J / Lord, Christopher J

Current opinion in genetics & development

2019 Volume 54, Page(s) 55–63

Abstract: The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now ... ...

Abstract	The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now been approved for use in a wider group of gynaecological cancers as well as for the treatment of BRCA-gene mutant breast cancer. Despite these advances, resistance to PARPi is a common clinical phenotype. Understanding, at the molecular level, how tumour cells respond to PARPi has the potential to inform how these drugs should be used clinically and since the discovery of this drug class, multiple different functional genomic strategies have been employed to dissect PARPi sensitivity and resistance. These have included genetic perturbation via classical gene targeting, gene silencing by siRNA or shRNA or transposon mutagenesis techniques. Recently, CRISPR-Cas9-based mutagenesis has greatly expanded the available range of relevant preclinical models and the precision of mutagenesis. Here, we review how these approaches have been used either in low-throughput, hypothesis-testing experiments or in the setting of large, hypothesis-generating, genetic screens aimed at understanding the molecular basis of PARPi sensitivity and resistance.
MeSH term(s)	BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Drug Resistance, Neoplasm/genetics ; Female ; Germ-Line Mutation/genetics ; Humans ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Phthalazines/therapeutic use ; Piperazines/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2019-04-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2019.03.001
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Article ; Online: Trends in Racial, Ethnic, and Gender Diversity in Orthopedic Surgery Spine Fellowships From 2007 to 2021.

Trenchfield, Delano / Murdock, Christopher J / Destine, Henson / Jain, Amit / Lord, Elizabeth / Aiyer, Amiethab

Spine

2023 Volume 48, Issue 20, Page(s) E349–E354

Abstract: Study design: Descriptive.: Objective: The objective of this study is to analyze trends in racial, ethnic, and gender diversity in orthopedic spine surgery fellowship trainees.: Summary of background data: Orthopedic surgery has consistently been ... ...

Abstract	Study design: Descriptive. Objective: The objective of this study is to analyze trends in racial, ethnic, and gender diversity in orthopedic spine surgery fellowship trainees. Summary of background data: Orthopedic surgery has consistently been labeled as one of the least diverse fields in Medicine. Although some effort has been made to combat this in recent years at the residency level, it is uncertain whether spine fellowships have had any changes in fellow demographics. Materials and methods: Fellowship demographic data were collected through the Accreditation Council for Graduate Medical Education. Data collected included gender (male, female, and not reported) and race (White, Asian, Black, Hispanic, Native Hawaiians, American Indian or Alaskan Native, other, and unknown). Percentage equivalents were calculated for each group from 2007 to 2008 to 2020 to 2021. A χ 2 test for trend (Cochran-Armitage test) was done to determine whether there was a significant change in percentages of each race and gender during the study period. The results were considered statistically significant at P <0.05. Results: White, Non-Hispanic males represent the largest proportion of orthopedic spine fellowship positions each year. From 2007 to 2021, there were no significant changes in the representation of any race or gender of orthopedic spine fellows. Males ranged from 81% to 95%, Whites from 28% to 66%, Asians from 9% to 28%, Blacks from 3% to 16%, and Hispanics from 0% to 10%. Native Hawaiians and American Indians remained at 0% for all years included in the study. Females and all races, excluding Whites, continue to be under-represented in orthopedic spine fellowship. Conclusions: Orthopedic spine surgery fellowship programs have not made substantial progress in diversifying its population. More attention is needed to increase diversity in residency programs through pipeline programs, increased mentorship and sponsorship, and early exposure to the field. Level of evidence: 1.
MeSH term(s)	Female ; Humans ; Male ; Education, Medical, Graduate/statistics & numerical data ; Fellowships and Scholarships/statistics & numerical data ; Hispanic or Latino/education ; Hispanic or Latino/statistics & numerical data ; Internship and Residency/statistics & numerical data ; Orthopedic Procedures/education ; United States/epidemiology ; Orthopedics/statistics & numerical data ; Spine/surgery ; Ethnicity/education ; Ethnicity/statistics & numerical data ; Racial Groups/education ; Racial Groups/ethnology ; Racial Groups/statistics & numerical data ; Sex Factors ; Race Factors
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	752024-4
ISSN	1528-1159 ; 0362-2436
ISSN (online)	1528-1159
ISSN	0362-2436
DOI	10.1097/BRS.0000000000004633
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