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Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma

Alan Van Goethem, Nurten Yigit UGent, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Franki Speleman UGent, Jason Shohet, Jo Vandesompele UGent and Tom Van Maerken UGent (2017) ONCOTARGET. 8(34). p.57047-57057
abstract
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
neuroblastoma, idasanutlin, p53, venetoclax, synergism, P53 PATHWAY, SENSITIZES NEUROBLASTOMA, ANTAGONIST NUTLIN-3, ANTITUMOR-ACTIVITY, CHEMOTHERAPY, RESISTANCE, COMBINATION, MECHANISM, LEUKEMIA, GROWTH
journal title
ONCOTARGET
Oncotarget
volume
8
issue
34
pages
57047 - 57057
Web of Science type
Article
Web of Science id
000408135600106
ISSN
1949-2553
DOI
10.18632/oncotarget.18982
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
8538409
handle
http://hdl.handle.net/1854/LU-8538409
date created
2017-11-21 17:54:26
date last changed
2017-12-14 10:06:19
@article{8538409,
  abstract     = {Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.},
  author       = {Van Goethem, Alan and Yigit, Nurten and Moreno-Smith, Myrthala and Vasudevan, Sanjeev A and Barbieri, Eveline and Speleman, Franki and Shohet, Jason and Vandesompele, Jo and Van Maerken, Tom},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {neuroblastoma,idasanutlin,p53,venetoclax,synergism,P53 PATHWAY,SENSITIZES NEUROBLASTOMA,ANTAGONIST NUTLIN-3,ANTITUMOR-ACTIVITY,CHEMOTHERAPY,RESISTANCE,COMBINATION,MECHANISM,LEUKEMIA,GROWTH},
  language     = {eng},
  number       = {34},
  pages        = {57047--57057},
  title        = {Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma},
  url          = {http://dx.doi.org/10.18632/oncotarget.18982},
  volume       = {8},
  year         = {2017},
}

Chicago
Van Goethem, Alan, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Franki Speleman, Jason Shohet, Jo Vandesompele, and Tom Van Maerken. 2017. “Dual Targeting of MDM2 and BCL2 as a Therapeutic Strategy in Neuroblastoma.” Oncotarget 8 (34): 57047–57057.
APA
Van Goethem, A., Yigit, N., Moreno-Smith, M., Vasudevan, S. A., Barbieri, E., Speleman, F., Shohet, J., et al. (2017). Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. ONCOTARGET, 8(34), 57047–57057.
Vancouver
1.
Van Goethem A, Yigit N, Moreno-Smith M, Vasudevan SA, Barbieri E, Speleman F, et al. Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. ONCOTARGET. 2017;8(34):57047–57.
MLA
Van Goethem, Alan, Nurten Yigit, Myrthala Moreno-Smith, et al. “Dual Targeting of MDM2 and BCL2 as a Therapeutic Strategy in Neuroblastoma.” ONCOTARGET 8.34 (2017): 57047–57057. Print.