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 8–10 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 (PPTP) 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 to the group median response using established response criteria. A total of 2134 comparisons were made. The single tumor response accurately predicted the group median response in 1604 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 mis-prediction 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.

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models

“…Our prior studies in the PPTP also suggest that in the absence of a known activating event (e.g., BRAF in astrocytoma or ALK activation in neuroblastoma), the response rate for signaling inhibitors is low (reviewed in Ref. ). For example, lapatinib an inhibitor of ERBB2 had very modest antitumor activity with no tumor regressions in 41 xenograft models tested at dose levels of drug giving clinically relevant exposures .…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…Ideally, OS research would use a more integrated approach, testing novel regimens across collections of diverse models, with laboratory experiments that educate human clinical trials 91 and canine clinical trials, 40,44 and vice versa. Each study, each experiment designed to answer important questions pertinent to that approach, all informing the ongoing development of future human studies by optimizing dose, schedule, biomarkers for inclusion/exclusion, and the thoughtful implementation of meaningful correlative studies.…”

Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field

“…In both cases, investigators determined that using the one animal per cohort study design has outstanding reproducibility for data collected. A very comprehensive study in a panel of pediatric tumors [ 88 ] substantially analyzed the individual tumor response by taking a randomly chosen mouse and compared the response to the group median. Allowing for the misprediction of +/− one response category (stable disease, partial response, complete response), the overall mean correct single mouse prediction rate was 95.28% and predicted overall object response rates for group data in 66 of 67 drug studies.…”

“…This has been most comprehensively demonstrated in a study where 62 treatments were assessed across six indications comprised of 29–45 models per indication [ 1 ]. The MCT approach has also proven to be elucidate potentially promising drugs in a “phase II” like study using B-ALL (B-cell acute lymphoblastic leukemia) PDXs 10 pediatric studies [ 12 , 88 ], and a breast PDX panel [ 15 ] among others. Consequently, this approach has now been adapted by many pharmaceutical companies [ 89 ], many of whom use CROs with extensive PDX collections to perform such studies.…”