Evidence map›Paper›PMID 31092693›Full record

ArticleScience translational medicine2019

Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51.

Alanna R Kaplan, Susan E Gueble, Yanfeng Liu, Sebastian Oeck, Hoon Kim, Zhong Yun, Peter M Glazer

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
98citing papers in PubMed, 3 pooled it
8.7field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

98 citing papers in PubMed, 3 syntheses or guidelines pooled it, 153 citations in OpenAlex.

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38 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors at 1 institution in 1 country.

Alanna R KaplanDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.ORCID 0000-0002-2612-4736
Susan E GuebleDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.ORCID 0000-0002-8043-1147
Yanfeng LiuDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.
Sebastian OeckDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.ORCID 0000-0001-9695-8771
Hoon KimDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.
Zhong YunDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.ORCID 0000-0003-4123-747X
Peter M GlazerDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA. peter.glazer@yale.edu.ORCID 0000-0003-4525-5560
Yale University · US

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007205 · NIGMS · YALE UNIVERSITY · PI KAZMIERCZAK, BARBARA I · 1985 to 2019
$42.9M
Targeting DNA Repair for Cancer Therapy.R35CA197574 · NCI · YALE UNIVERSITY · PI PETER M GLAZER · 2017 to 2026
$8.6M
Oncometabolites, DNA Repair, and CancerR01ES005775 · NIEHS · YALE UNIVERSITY · PI PETER M GLAZER · 1998 to 2026
$8.0M
Malignant and Radioresistant Nature of Hypoxic Tumor CellsR01CA178254 · NCI · YALE UNIVERSITY · PI YUN, ZHONG · 2014 to 2018
$1.7M
Tumor-selective inhibition of DNA repair using pHLIPF30CA221065 · NCI · YALE UNIVERSITY · PI KAPLAN, ALANNA · 2018 to 2020
$105k
NCI NIH HHS F30 CA221065NCI NIH HHS R01 CA178254NCI NIH HHS R35 CA197574NIEHS NIH HHS R01 ES005775NIGMS NIH HHS T32 GM007205
6 · The paper itself

Abstract

Combining the anti-angiogenic agent cediranib with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib improves progression-free survival compared to olaparib alone in ovarian cancer patients through an unknown mechanism. PARP inhibitors are used primarily in the treatment of patients with DNA repair-associated (BRCA1/2) mutated cancers because these mutations cause a deficit in homology-directed DNA repair (HDR) that confers sensitivity to these agents. However, the combination of cediranib and olaparib was effective in patients without BRCA1/2 mutations. We report here that cediranib confers sensitivity to olaparib by down-regulating HDR in tumor cells. This occurs partially as a result of cediranib inducing hypoxia, which suppresses expression of the HDR factors BRCA1/2 and RAD51 recombinase (RAD51). However, we also observed that cediranib has a direct effect on HDR independent of its ability to induce tumor hypoxia. This direct effect occurs through platelet-derived growth factor receptor (PDGFR) inhibition, activation of protein phosphatase 2A (PP2A), and E2F transcription factor 4 (E2F4)/RB transcriptional corepressor like 2 (RB2/p130)-mediated repression of

Indexed as

AnimalsBRCA1 ProteinBRCA2 ProteinCell Line, TumorDNA RepairDown-RegulationE2F4 Transcription FactorFemaleGene Expression Regulation, NeoplasticHumansIndolesMice, NudePoly(ADP-ribose) Polymerase InhibitorsQuinazolinesRad51 RecombinaseReceptors, Platelet-Derived Growth FactorBRCA1 ProteinBRCA2 ProteincediranibE2F4 Transcription FactorIndolesPoly(ADP-ribose) Polymerase InhibitorsQuinazolinesRad51 RecombinaseReceptors, Platelet-Derived Growth FactorVascular Endothelial Growth Factor Receptor-2

Identifiers

PMID31092693
PMCPMC6626544
OpenAlexW2946425279

What OpenQuestion holds

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LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.