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PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma

Overview of attention for article published in Journal of Translational Medicine, March 2016
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Title
PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma
Published in
Journal of Translational Medicine, March 2016
DOI 10.1186/s12967-016-0814-z
Pubmed ID
Authors

Yael Babichev, Leah Kabaroff, Alessandro Datti, David Uehling, Methvin Isaac, Rima Al-awar, Michael Prakesch, Ren X. Sun, Paul C. Boutros, Rosemarie Venier, Brendan C. Dickson, Rebecca A. Gladdy

Abstract

Leiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth. LMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts. Compounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone. In summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 36 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 36 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 8 22%
Researcher 7 19%
Student > Bachelor 3 8%
Student > Postgraduate 3 8%
Other 2 6%
Other 4 11%
Unknown 9 25%
Readers by discipline Count As %
Medicine and Dentistry 10 28%
Biochemistry, Genetics and Molecular Biology 9 25%
Agricultural and Biological Sciences 6 17%
Psychology 2 6%
Unknown 9 25%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 March 2016.
All research outputs
#3,783,135
of 7,372,759 outputs
Outputs from Journal of Translational Medicine
#944
of 1,700 outputs
Outputs of similar age
#151,046
of 279,041 outputs
Outputs of similar age from Journal of Translational Medicine
#38
of 71 outputs
Altmetric has tracked 7,372,759 research outputs across all sources so far. This one is in the 28th percentile – i.e., 28% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,700 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.0. This one is in the 13th percentile – i.e., 13% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 279,041 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 35th percentile – i.e., 35% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 71 others from the same source and published within six weeks on either side of this one. This one is in the 2nd percentile – i.e., 2% of its contemporaries scored the same or lower than it.