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Cancer Res. 2016 Oct 1;76(19):5798-5809. Epub 2016 Aug 5.

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.

Author information

1
Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2
Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
3
Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware.
4
Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, New York.
5
Department of Internal Medicine and Pediatrics, Texas Tech University Health Sciences Center, Lubbock, Texas.
6
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.
7
Department of Surgery, Duke University Medical Center, Durham, North Carolina.
8
Department of Molecular Medicine, Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, Texas.
9
Biostatistics, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
10
Department of Biostatistics St. Jude Children's Research Hospital, Memphis, Tennessee.
11
Clinical Investigations Branch, Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
12
Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
13
Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio. houghtonp@uthscsa.edu.

Abstract

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809.

PMID:
27496711
PMCID:
PMC5050128
DOI:
10.1158/0008-5472.CAN-16-0122
[Indexed for MEDLINE]
Free PMC Article

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