title: Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.
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. ©2016 AACR.
authors: Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
authors: Brendan
authors: B
authors: Murphy
authors: Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
authors: Han
authors: H
authors: Yin
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
authors: John M
authors: JM
authors: Maris
authors: Department of Pediatrics, A.I. duPont Hospital for Children, Wilmington, Delaware.
authors: E Anders
authors: EA
authors: Kolb
authors: Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, New York.
authors: Richard
authors: R
authors: Gorlick
authors: Department of Internal Medicine and Pediatrics, Texas Tech University Health Sciences Center, Lubbock, Texas.
authors: C Patrick
authors: CP
authors: Reynolds
authors: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.
authors: Min H
authors: MH
authors: Kang
authors: Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors: Stephen T
authors: ST
authors: Keir
authors: Department of Molecular Medicine, Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, Texas.
authors: Raushan T
authors: RT
authors: Kurmasheva
authors: Biostatistics, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
authors: Igor
authors: I
authors: Dvorchik
authors: Department of Biostatistics St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Jianrong
authors: J
authors: Wu
authors: Department of Biostatistics St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Catherine A
authors: CA
authors: Billups
authors: Department of Biostatistics St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Nana
authors: N
authors: Boateng
authors: Clinical Investigations Branch, Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
authors: Malcolm A
authors: MA
authors: Smith
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Richard B
authors: RB
authors: Lock
authors: Center for Childhood Cancer and Blood Diseases, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio. houghtonp@uthscsa.edu.
authors: Peter J
authors: PJ
authors: Houghton
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012189:Retrospective Studies; D023041:Xenograft Model Antitumor Assays / Q000379:methods*