Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program†
Christopher L. Morton BS
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorJohn M. Maris MD
Children's Hospital of Philadelphia, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorStephen T. Keir PhD
Duke University Medical Center, Durham, North Carolina
Search for more papers by this authorRichard Gorlick MD
The Children's Hospital at Montefiore, Bronx, New York
Search for more papers by this authorE. Anders Kolb MD
A.I. duPont Hospital for Children, Wilmington, Delaware
Search for more papers by this authorCatherine A. Billups MS
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorJianrong Wu PhD
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorMalcolm A. Smith MD, PhD
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland
Search for more papers by this authorCorresponding Author
Peter J. Houghton PhD
Nationwide Children's Hospital, Columbus, Ohio
Center for Childhood Cancer, The Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205.===Search for more papers by this authorChristopher L. Morton BS
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorJohn M. Maris MD
Children's Hospital of Philadelphia, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorStephen T. Keir PhD
Duke University Medical Center, Durham, North Carolina
Search for more papers by this authorRichard Gorlick MD
The Children's Hospital at Montefiore, Bronx, New York
Search for more papers by this authorE. Anders Kolb MD
A.I. duPont Hospital for Children, Wilmington, Delaware
Search for more papers by this authorCatherine A. Billups MS
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorJianrong Wu PhD
St. Jude Children's Research Hospital, Memphis, Tennessee
Search for more papers by this authorMalcolm A. Smith MD, PhD
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland
Search for more papers by this authorCorresponding Author
Peter J. Houghton PhD
Nationwide Children's Hospital, Columbus, Ohio
Center for Childhood Cancer, The Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205.===Search for more papers by this authorConflict of interest: Nothing to declare.
Abstract
Background
Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings.
Procedures
Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models).
Results
The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine–cediranib combination). The cediranib–cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra-additive with rapamycin in four models, although the effects were not large.
Conclusions
Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination. Pediatr Blood Cancer 2012; 58: 566–571. © 2011 Wiley Periodicals, Inc.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| PBC_23159_sm_SuppDef.doc51.5 KB | Supplementary Definitions |
| PBC_23159_sm_SuppTabI.doc74.5 KB | Supplementary Table I |
| PBC_23159_sm_SuppTabII.doc226.5 KB | Supplementary Table II |
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