Jones Luke, Richmond Jennifer, Evans Kathryn, Carol Hernan, Jing Duohui, Kurmasheva Raushan T, Billups Catherine A, Houghton Peter J, Smith Malcolm A, Lock Richard B
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Clin Cancer Res. 2017 Jul 15;23(14):3744-3755. doi: 10.1158/1078-0432.CCR-16-2392. Epub 2017 Jan 24.
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. ALL PDXs were lentivirally transduced to stably express luciferase and green fluorescent protein. PDX responses to an induction-type regimen of vincristine, dexamethasone, and -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. 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. 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. .
强大的小儿急性淋巴细胞白血病（ALL）临床前模型对于确定有前景的疗法以用于高危患者的临床评估至关重要。ALL的患者来源异种移植（PDX）模型为评估新药提供了一个临床相关平台，其疗效通常通过计数小鼠外周血（PB）中循环的人类淋巴母细胞作为疾病负担的指标来评估。虽然这种技术可以实时间接测量疾病负担，但无法评估治疗对体内疾病病灶的影响。我们探讨了生物发光成像（BLI）与PB监测相比在评估ALL PDX药物反应方面的优势。还探索了基于BLI的药物反应阈值。ALL PDX通过慢病毒转导稳定表达荧光素酶和绿色荧光蛋白。通过BLI和PB评估PDX对长春新碱、地塞米松和门冬酰胺酶诱导方案的反应。在治疗开始后第28天，通过对主要器官的流式细胞术分析评估残留疾病。随后使用BLI和PB评估Bcl-2抑制剂维奈克拉的疗效。与PB相比，BLI大大加速并增强了白血病负担的检测，并以定量方式确定了治疗期间残留疾病的部位，突出了当前基于PB的评分标准的局限性。通过将BLI与PB和骨髓中人类淋巴母细胞的计数相结合，我们能够重新定义类似于临床环境的反应标准。BLI显著提高了小儿ALL PDX临床前药物测试的严格性，这对于确定用于临床评估的有效药物可能很重要。
