Evidence map›Paper›PMID 22896656›Full record

ArticleClinical cancer research : an official journal of the American Association for Cancer Research2012

Src Inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo.

Fiona Simpkins, Pedro Hevia-Paez, Jun Sun, Wendy Ullmer, Candace A Gilbert, Thiago da Silva, Ali Pedram, Ellis R Levin, Isildinha M Reis, Brian Rabinovich and 8 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.

0numbers the graph read from it
0cells of the map it votes in
39citing papers in PubMed
2.4field-weighted citation impact, top 11% 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

39 citing papers in PubMed, 62 citations in OpenAlex.

  1. Article
  2. Review
  3. Advances in ovarian tumor stem cells and therapy.Cell biochemistry and biophysics · 2024
    Review
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  6. Observational
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  20. Dual Src and MEK Inhibition Decreases Ovarian Cancer Growth and Targets Tumor Initiating Stem-Like Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 3 institutions in 1 country.

Fiona SimpkinsBraman Family Breast Cancer Institute and Division of Biostatistics, Department of Epidemiology and Public Health, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Pedro Hevia-Paez
Jun Sun
Wendy Ullmer
Candace A Gilbert
Thiago da Silva
Ali Pedram
Ellis R Levin
Isildinha M Reis
Brian Rabinovich
Diana Azzam
Xiang-Xi Xu
Tan A Ince
Ji-Yeon Yang
Roel G W Verhaak
Yiling Lu
Gordon B Mills
Joyce M Slingerland
University of California, Irvine · USSylvester Comprehensive Cancer Center · USUniversity of Miami · US

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8M
Targeting the PI3K Signaling Pathway in Endometrial CarcinomaP50CA098258 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BODURKA, DIANE · 2003 to 2020
$32.0M
Ovarian Cancer: Epithelial DedifferentiationR01CA079716 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI XU, XIANGXI MIKE · 1999 to 2015
$4.8M
Non-genomic actions of estrogen in breast cancerR01CA100366 · NCI · SOUTHERN CALIFORNIA INST FOR RES/EDUC · PI LEVIN, ELLIS R · 2004 to 2014
$2.3M
Mechanisms Whereby Src Activates Estrogen Stimulated ER Proteolysis and ER TargetR01CA123415 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI SLINGERLAND, JOYCE MARIE · 2009 to 2013
$1.6M
Targeting SRC Signaling Pathways to Promote Cell Cycle Arrest in Ovarian CancerK08CA151892 · NCI · UNIVERSITY OF PENNSYLVANIA · PI SIMPKINS, FIONA · 2011 to 2016
$807k
NCI NIH HHS K08 CA151892NCI NIH HHS NIH K 1K08CA151892-01NCI NIH HHS NIH-NCI1-R01-CA-123415-01NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA098258NCI NIH HHS R01 CA079716NCI NIH HHS R01 CA100366NCI NIH HHS R01 CA123415
6 · The paper itself

Abstract

purposeMore effective, less toxic treatments for recurrent ovarian cancer are needed. Although more than 60% of ovarian cancers express the estrogen receptor (ER), ER-targeted drugs have been disappointing due to drug resistance. In other estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell-cycle progression. Because Src is activated in most ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent antiestrogen resistance. EXPERIMENTAL

designER and Src were assayed in 338 primary ovarian cancers. Dual ER and Src blockade effects on cell cycle, ER target gene expression, and survival were assayed in ERα+ ovarian cancer lines, a primary human ovarian cancer culture in vitro, and on xenograft growth.

resultsMost primary ovarian cancers express ER. Src activity was greater in ovarian cancer lines than normal epithelial lines. Estrogen activated Src, ER-Src binding, and ER translocation from cytoplasm to nucleus. Estrogen-mediated mitogenesis was via ERα, not ERβ. While each alone had little effect, combined saracatinib and fulvestrant increased p27 and inhibited cyclin E-Cdk2 and cell-cycle progression. Saracatinib also impaired induction of ER-target genes c-Myc and FOSL1; this was greatest with dual therapy. Combined therapy induced autophagy and more effectively inhibited ovarian cancer xenograft growth than monotherapy.

conclusionsSaracatinib augments effects of fulvestrant by opposing estrogen-mediated Src activation and target gene expression, increasing cell-cycle arrest, and impairing survival, all of which would oppose antiestrogen resistance in these ER+ ovarian cancer models. These data support further preclinical and clinical evaluation of combined fulvestrant and saracatinib in ovarian cancer.

Indexed as

Drug Resistance, NeoplasmAnimalsAntineoplastic AgentsApoptosisBenzodioxolesCell Line, TumorCell NucleusCell ProliferationDisease Models, AnimalEnzyme ActivationEstradiolEstrogensFemaleFulvestrantGene Expression Regulation, NeoplasticGene Knockdown TechniquesAntineoplastic AgentsBenzodioxolesEstradiolEstrogensFulvestrantQuinazolinesReceptors, Estrogensaracatinibsrc-Family Kinases

Identifiers

PMID22896656
PMCPMC3698880
OpenAlexW2120064499

What OpenQuestion holds

Textmetadata
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.