Ewing sarcoma;
drug synergism;
p53;
tumour growth;
zebrafish;
anti-cancer drug screen;
molecular targeted therapy;
TRANSGENIC ZEBRAFISH MODEL;
DRUG DISCOVERY;
CYTOGENETIC CHARACTERIZATION;
CANCER MODEL;
CELL-LINES;
TUMORS;
EXPRESSION;
SYSTEM;
GENE;
MDM2;
D O I:
10.1002/path.4378
中图分类号:
R73 [肿瘤学];
学科分类号:
100214 ;
摘要:
Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Amatruda, JF
;
Shepard, JL
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Shepard, JL
;
Stern, HM
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Stern, HM
;
Zon, LI
论文数: 0引用数: 0
h-index: 0
机构:
Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USAChildrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
机构:
Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USAChildrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Balamuth, Naomi J.
;
Womer, Richard B.
论文数: 0引用数: 0
h-index: 0
机构:
Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USAChildrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
机构:
St James Univ Hosp, Leeds Inst Mol Med, Canc Res UK Clin Ctr, Candlelighters Childrens Canc Res Grp, Leeds LS9 7TF, W Yorkshire, EnglandSt James Univ Hosp, Leeds Inst Mol Med, Canc Res UK Clin Ctr, Candlelighters Childrens Canc Res Grp, Leeds LS9 7TF, W Yorkshire, England
机构:
Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, Preclin Pharmacol Core Lab, New York, NY 10021 USAMem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, Preclin Pharmacol Core Lab, New York, NY 10021 USA
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Amatruda, JF
;
Shepard, JL
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Shepard, JL
;
Stern, HM
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
Stern, HM
;
Zon, LI
论文数: 0引用数: 0
h-index: 0
机构:
Childrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USAChildrens Hosp, Howard Hughes Med Inst, Dept Hematol Oncol, Boston, MA 02115 USA
机构:
Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USAChildrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Balamuth, Naomi J.
;
Womer, Richard B.
论文数: 0引用数: 0
h-index: 0
机构:
Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USAChildrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
机构:
St James Univ Hosp, Leeds Inst Mol Med, Canc Res UK Clin Ctr, Candlelighters Childrens Canc Res Grp, Leeds LS9 7TF, W Yorkshire, EnglandSt James Univ Hosp, Leeds Inst Mol Med, Canc Res UK Clin Ctr, Candlelighters Childrens Canc Res Grp, Leeds LS9 7TF, W Yorkshire, England
机构:
Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, Preclin Pharmacol Core Lab, New York, NY 10021 USAMem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, Preclin Pharmacol Core Lab, New York, NY 10021 USA