Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.

Jones, L; Richmond, J; Evans, K; Carol, H; Jing, D; Kurmasheva, RT; Billups, CA; Houghton, PJ; Smith, MA; Lock, RB

Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.

Jones, L Richmond, J Evans, K Carol, H Jing, D

Kurmasheva, RT Billups, CA Houghton, PJ Smith, MA Lock, RB

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Publisher:: American Association for Cancer Research
Publication Type:: Journal Article
Citation:: Clinical Cancer Research, 2017, 23, (14), pp. 3744-3755
Issue Date:: 2017-07-15

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Field	Value	Language
dc.contributor.author	Jones, L
dc.contributor.author	Richmond, J
dc.contributor.author	Evans, K
dc.contributor.author	Carol, H
dc.contributor.author	Jing, D https://orcid.org/0000-0002-1491-8002
dc.contributor.author	Kurmasheva, RT
dc.contributor.author	Billups, CA
dc.contributor.author	Houghton, PJ
dc.contributor.author	Smith, MA
dc.contributor.author	Lock, RB
dc.date.accessioned	2022-09-16T04:25:41Z
dc.date.available	2017-01-12
dc.date.available	2022-09-16T04:25:41Z
dc.date.issued	2017-07-15
dc.identifier.citation	Clinical Cancer Research, 2017, 23, (14), pp. 3744-3755
dc.identifier.issn	1078-0432
dc.identifier.issn	1557-3265
dc.identifier.uri	http://hdl.handle.net/10453/161852
dc.description.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 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. Clin Cancer Res; 23(14); 3744-55. ©2017 AACR.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for Cancer Research
dc.relation.ispartof	Clinical Cancer Research
dc.relation.isbasedon	10.1158/1078-0432.CCR-16-2392
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Diagnostic Imaging
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Flow Cytometry
dc.subject.mesh	Green Fluorescent Proteins
dc.subject.mesh	Humans
dc.subject.mesh	Lentivirus
dc.subject.mesh	Luciferases
dc.subject.mesh	Luminescent Measurements
dc.subject.mesh	Mice
dc.subject.mesh	Neoplastic Cells, Circulating
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Animals
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Diagnostic Imaging
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Flow Cytometry
dc.subject.mesh	Green Fluorescent Proteins
dc.subject.mesh	Humans
dc.subject.mesh	Lentivirus
dc.subject.mesh	Luciferases
dc.subject.mesh	Luminescent Measurements
dc.subject.mesh	Mice
dc.subject.mesh	Neoplastic Cells, Circulating
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Lentivirus
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Luciferases
dc.subject.mesh	Green Fluorescent Proteins
dc.subject.mesh	Diagnostic Imaging
dc.subject.mesh	Luminescent Measurements
dc.subject.mesh	Flow Cytometry
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Neoplastic Cells, Circulating
dc.title	Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.
dc.type	Journal Article
utslib.citation.volume	23
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-09-16T04:25:40Z
pubs.issue	14
pubs.publication-status	Published
pubs.volume	23
utslib.citation.issue	14

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 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. Clin Cancer Res; 23(14); 3744-55. ©2017 AACR.

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http://hdl.handle.net/10453/161852