TY - JOUR
T1 - Bioluminescence imaging enhances analysis of drug responses in a patient-derived xenograft model of pediatric ALL
AU - Jones, Luke
AU - Richmond, Jennifer
AU - Evans, Kathryn
AU - Carol, Hernan
AU - Jing, Duohui
AU - Kurmasheva, Raushan T.
AU - Billups, Catherine A.
AU - Houghton, Peter J.
AU - Smith, Malcolm A.
AU - Lock, Richard B.
N1 - Funding Information:
The authors thank AbbVie Inc. for providing venetoclax (ABT-199), as well as Dr. Tzong-tyng Hung, Dr. Brendan Lee, and Dr. Carl Power of the Biological Resources Imaging Laboratory at the University of New South Wales for their bioluminescence imaging support and equipment. Children's Cancer Institute is affiliated with UNSW Australia and the Sydney Children's Hospitals Network. This work was partially supported by grants from the National Institutes of Health and National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03), and the National Health and Medical Research Council of Australia (NHMRC). R.B. Lock is supported by a fellowship from the NHMRC. L. Jones was supported by an Australian Postgraduate Award from the Australian Government Department of Education and Training. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - 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 vivo PDX responses to an induction-type regimen of vincristine, dexamethasone, and L-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.
AB - 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 vivo PDX responses to an induction-type regimen of vincristine, dexamethasone, and L-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.
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U2 - 10.1158/1078-0432.CCR-16-2392
DO - 10.1158/1078-0432.CCR-16-2392
M3 - Article
C2 - 28119366
AN - SCOPUS:85024128971
VL - 23
SP - 3744
EP - 3755
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 14
ER -