title: Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.
abstract: Purpose:Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing promising therapies for clinical assessment in high-risk patients. Patient-derived xenograft (PDX) models of ALL provide a clinically relevant platform for assessing novel drugs, with efficacy generally assessed by enumerating circulating human lymphoblasts in mouse peripheral blood (PB) as an indicator of disease burden. While allowing indirect measurement of disease burden in real time, this technique cannot assess treatment effects on internal reservoirs of disease. We explore benefits of bioluminescence imaging (BLI) to evaluate drug responses in ALL PDXs, compared with PB monitoring. BLI-based thresholds of drug response are also explored.Experimental Design:ALL PDXs were lentivirally transduced to stably express luciferase and green fluorescent protein.In vivoPDX responses to an induction-type regimen of vincristine, dexamethasone, andL-asparaginase were assessed by BLI and PB. Residual disease at day 28 after treatment initiation was assessed by flow cytometric analysis of major organs. BLI and PB were subsequently used to evaluate efficacy of the Bcl-2 inhibitor venetoclax.Results:BLI considerably accelerated and enhanced detection of leukemia burden compared with PB and identified sites of residual disease during treatment in a quantitative manner, highlighting limitations in current PB-based scoring criteria. Using BLI alongside enumeration of human lymphoblasts in PB and bone marrow, we were able to redefine response criteria analogous to the clinical setting.Conclusions:BLI substantially improves the stringency of preclinical drug testing in pediatric ALL PDXs, which will likely be important in prioritizing effective agents for clinical assessment.Clin Cancer Res; 23(14); 3744-55. ©2017 AACR.
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Jones
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richmond
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Duohui
authors.initials: D
authors.lastname: Jing
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia. rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008163:Luminescent Measurements; D051379:Mice; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D008156:Luciferases