高通量筛选作为一种对儿科B细胞前体急性淋巴细胞白血病不良预后亚群的药物重定位策略。
High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia.
发表日期：2023 Sep 15
作者：
Athanasios Oikonomou, Luigia Valsecchi, Manuel Quadri, Titus Watrin, Katerina Scharov, Simona Procopio, Jia-Wey Tu, Melina Vogt, Angela Maria Savino, Daniela Silvestri, Maria Grazia Valsecchi, Andrea Biondi, Arndt Borkhardt, Sanil Bhatia, Giovanni Cazzaniga, Grazia Fazio, Michela Bardini, Chiara Palmi
来源：
BIOCHEMICAL PHARMACOLOGY
摘要：
尽管儿童BCP-ALL的治愈率已经达到了很高的水平，但约有15%的患者对常规化疗无响应并经历疾病复发。通过强化治疗来提高治愈率的主要努力会导致治疗相关毒性和死亡率不可接受的增加，因此需要寻找新的治疗方法。高通量（HTP）药物筛选可以在体外对患者的反应进行分析，并可以重新应用于其他疾病的化合物，这些化合物可以立即用于临床应用。本研究旨在应用HTP药物筛选来鉴定对于预后较差的儿童BCP-ALL患者（如携带Down综合征（DS）或涉及PAX5或KMT2A/MLL基因重排的患者）可能有效的化合物。采用半自动化的HTP药物筛选平台，在34例BCP-ALL患者（9例DS CRLF2r，15例PAX5r，10例MLLr）的患者源性异种移植物（PDX）样品、7例人类BCP-ALL细胞系和14例造血健康供体样品上进行了一个174种化合物库（FDA/EMA批准或处于临床前研究中）的筛选。我们鉴定出了9种对BCP-ALL具有活性的化合物（ABT-199/venetoclax、AUY922/luminespib、地塞米松、EC144、JQ1、NVP-HSP990、紫杉醇、PF-04929113和长春新碱），但对正常细胞无损害。体外验证结果确认，BCL2抑制剂venetoclax以纳摩尔浓度对所有三种ALL亚组均具有抗白血病作用。总体而言，本研究指出了应用HTP筛选进行药物重新应用的益处，以便为难治性儿童BCP-ALL亚组筛选出有效且可在临床上应用的治疗药物。版权所有 © 2023 Elsevier Inc.
Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients' responses in vitro and allows the repurposing of compounds currently used for other diseases, which can be immediately available for clinical application. The aim of this study was to apply HTP drug screening to identify potentially effective compounds for the treatment of pediatric BCP-ALL patients with poor prognosis, such as patients with Down Syndrome (DS) or carrying rearrangements involving PAX5 or KMT2A/MLL genes. Patient-derived Xenografts (PDX) samples from 34 BCP-ALL patients (9 DS CRLF2r, 15 PAX5r, 10 MLLr), 7 human BCP-ALL cell lines and 14 hematopoietic healthy donor samples were screened on a semi-automated HTP drug screening platform using a 174 compound library (FDA/EMA-approved or in preclinical studies). We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.Copyright © 2023. Published by Elsevier Inc.