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Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma

Overview of attention for article published in BMC Cancer, February 2016
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Title
Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma
Published in
BMC Cancer, February 2016
DOI 10.1186/s12885-016-2129-0
Pubmed ID
Authors

Rachel Tanos, Dipan Karmali, Srilatha Nalluri, Kelly C. Goldsmith

Abstract

Pediatric patients with high-risk neuroblastoma (HR NB) often fail to respond to upfront intensive multimodal therapy. Tumor-acquired suppression of apoptosis contributes to therapy resistance. Many HR NB tumors depend on the anti-apoptotic protein Bcl-2 for survival, through Bcl-2 sequestration and inhibition of the pro-apoptotic protein, Bim. Bcl-2 dependent xenografts derived from aggressive human NB tumors are cured with a combination of cyclophosphamide and ABT-737, a Bcl-2/Bcl-XL/Bcl-w small molecule antagonist. The oral analogue to ABT-737, Navitoclax (ABT-263), clinically causes an immediate drop in peripheral platelet counts as mature platelets depend on Bcl-xL for survival. This led to the creation of a Bcl-2 selective inhibitor, ABT-199 (Venetoclax). A Phase I trial of ABT-199 in CLL showed remarkable antitumor activity and stable patient platelet counts. Given Bcl-XL does not play a role in HR NB survival, we hypothesized that ABT-199 would be equally potent against HR NB. Cytotoxicity and apoptosis were measured in human derived NB cell lines exposed to ABT-199 combinations. Co-Immunoprecipitation evaluated Bim displacement from Bcl-2, following ABT-199. Murine xenografts of NB cell lines were grown and then exposed to a 14-day course of ABT-199 alone and with cyclophosphamide. Bcl-2 dependent NB cell lines are exquisitely sensitive to ABT-199 (IC50 1.5-5 nM) in vitro, where Mcl-1 dependent NBs are completely resistant. Treatment with ABT-199 displaces Bim from Bcl-2 in NB to activate caspase 3, confirming the restoration of mitochondrial apoptosis. Murine xenografts of Mcl-1 and Bcl-2 dependent NBs were treated with a two-week course of ABT-199, cyclophosphamide, or ABT-199/cyclophosphamide combination. Mcl-1 dependent tumors did not respond to ABT-199 alone and showed no significant difference in time to tumor progression between chemotherapy alone or ABT-199/cyclophosphamide combination. In contrast, Bcl-2 dependent xenografts responded to ABT-199 alone and had sustained complete remission (CR) to the ABT-199/cyclophosphamide combination, with one recurrent tumor maintaining Bcl-2 dependence and obtaining a second CR after a second course of therapy. HR NB patients are often thrombocytopenic at relapse, raising concerns for therapies like ABT-263 despite its HR NB tumor targeting potential. Our data confirms that Bcl-2 selective inhibitors like ABT-199 are equally potent in HR NB in vitro and in vivo and given their lack of platelet toxicity, should be translated into the clinic for HR NB.

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The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 35 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 3%
Unknown 34 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 9 26%
Researcher 5 14%
Student > Bachelor 5 14%
Other 2 6%
Student > Doctoral Student 2 6%
Other 4 11%
Unknown 8 23%
Readers by discipline Count As %
Medicine and Dentistry 7 20%
Biochemistry, Genetics and Molecular Biology 6 17%
Agricultural and Biological Sciences 4 11%
Pharmacology, Toxicology and Pharmaceutical Science 3 9%
Engineering 2 6%
Other 5 14%
Unknown 8 23%
Attention Score in Context

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 13 July 2016.
All research outputs
#15,359,595
of 22,849,304 outputs
Outputs from BMC Cancer
#4,114
of 8,314 outputs
Outputs of similar age
#236,563
of 400,824 outputs
Outputs of similar age from BMC Cancer
#86
of 181 outputs
Altmetric has tracked 22,849,304 research outputs across all sources so far. This one is in the 22nd percentile – i.e., 22% of other outputs scored the same or lower than it.
So far Altmetric has tracked 8,314 research outputs from this source. They receive a mean Attention Score of 4.3. This one is in the 40th percentile – i.e., 40% 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 400,824 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 31st percentile – i.e., 31% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 181 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.