Clonal Therapy for Pediatric T-cell Acute Lymphoblastic Leukemia

小儿 T 细胞急性淋巴细胞白血病的克隆治疗

• 批准号: 10683231
• 负责人: Jun J Yang
• 金额: $ 51.81万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683231
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Algorithms; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; BCL2 gene; CRISPR screen; Cancer Etiology; Cell Communication; Cell Lineage; Cell Maturation; Cells; Cessation of life; Child; Childhood; Childhood Precursor T Lymphoblastic Leukemia; Clinical Trials; Clonality; Clone Cells; Combination Drug Therapy; Communication; Dasatinib; Data; Dependence; Development; Developmental Process; Disease; Disease Outcome; Drug Combinations; Drug Screening; Drug Targeting; Drug resistance; Etiology; Exhibits; Genomics; Heterogeneity; In Vitro; Inferior; Knowledge; Ligands; Long-Term Survivors; Malignant Childhood Neoplasm; Maps; Mediating; Molecular; NOTCH3 gene; Network-based; Normal Cell; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Population; Positioning Attribute; Program Development; Proliferating; Recurrence; Recurrent disease; Refractory; Refractory Disease; Relapse; Resistance; Reverse engineering; Role; Saint Jude Children' s Research Hospital; Sampling; Signal Transduction; Survival Rate; System; Systems Biology; T cell differentiation; T-Cell Development; T-Lymphocyte; Testing; Treatment outcome; Validation; Work; burden of illness; cancer cell; cell fate specification; chemotherapy; drug sensitivity; improved; improved outcome; in vivo; inhibitor; intercellular communication; leukemia; leukemia treatment; migration; new therapeutic target; novel drug combination; novel therapeutic intervention; patient derived xenograft model; population based; programs; receptor; response; single cell analysis; single-cell RNA sequencing; success; targeted agent; targeted treatment; transcriptomics; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Pediatric T-cell acute lymphoblastic leukemia (pT-ALL), with limited treatment options, has been historically associated with inferior treatment outcomes with chemotherapy, compared to B-cell ALL. Despite the advances made in our understanding of the etiology of pT-ALL, the overall survival of this disease has not significantly improved. Children with recurrent T-ALL have a dismal survival rate of < 25%, and long-term survivors have an increased burden of disease associated with the curative chemotherapies they received. Therefore, novel targeted therapeutics in combinations are much needed. Population-based genomic and transcriptomic studies have revealed the inter-leukemia diversity of pT-ALL. However, very little is known about intra-leukemia clonal heterogeneity in pT-ALL that were known to contribute to drug resistance and disease recurrence. For example, it remains mysterious what molecular and cellular features of the rare clones have to allow them to survive treatment as other major clones are eliminated. T-ALL arises during the dynamic developmental processes and retains hallmarks of their cellular origins. However, it remains unclear how T-cell development contributes to clonal heterogeneity of pT-ALL. Moreover, whether cell–cell communications between cancer cells and normal cells in the tumor microenvironment contribute to disease recurrence is unclear. Using bulk systems pharmacology and single-cell systems biology approaches, we discovered the leukemia heterogeneity associated with T-cell maturation and drug sensitivity in single cells. Therefore, we hypothesize that clonal therapy by targeting signaling networks in clonal subpopulations arising from T-cell differentiation will minimize relapsed/refractory diseases and improve outcomes for pT-ALL. Our team at St. Jude is uniquely positioned to tackle these challenges, capitalizing on vast expertise in systems biology, ALL pharmacogenomics, and T-cell development. Specifically, in this proposal, we will determine how T-cell development contributes to the intra-leukemia heterogeneity in pT-ALL (Aim 1). We will map clones in pT-ALL to T-cell maturation stages by single-cell analyses of primary samples and normal developmental T cells. We will identify clone-specific hidden drivers that drive clonal heterogeneity and drug sensitivity. Next, we will identify drug combinations that target signaling drivers in multiple clones (Aim 2). We will integrate bulk systems pharmacology with single-cell hidden-driver analyses to unbiasedly predict synergistic drug combinations and validate them by drug screening. We will use patient-derived xenografts that retain clonal complexity for in vivo validation. We will also investigate how TME reprograming modulates clone selection with treatment in pT-ALL (Aim 3). We will reconstruct the tumor and TME communication network from scRNA-seq data and elucidate the molecular mechanisms of clonal selection with treatment in pT-ALL. Taken together, this project will address fundamental unanswered questions in intra- leukemia clonality and provide a new clonal therapy approach that eliminates multiple clones, including those that contribute to disease recurrence, thereby, improves the outcomes for children with T-ALL.

项目总结/摘要 儿童T细胞急性淋巴细胞白血病（pT-ALL）的治疗选择有限， 与B细胞ALL相比，化疗的治疗结果较差。尽管取得了进步 在我们对pT-ALL病因学的了解中，这种疾病的总生存率没有显著性差异， 提高复发性T-ALL儿童的存活率很低，<25%，长期存活者的存活率为25%。 与他们接受的治愈性化疗相关的疾病负担增加。因此，小说有针对性地 非常需要组合的治疗剂。基于人群的基因组学和转录组学研究 揭示了白血病间pT-ALL的多样性。然而，关于白血病细胞内克隆性 已知pT-ALL异质性导致耐药性和疾病复发。例如它 罕见克隆体的分子和细胞特征使它们能够在治疗中存活仍然是个谜 其他主要克隆体被淘汰T-ALL在动态发育过程中产生，并保留 细胞起源的标志然而，目前尚不清楚T细胞发育如何促进克隆性T细胞减少。 pT-ALL的异质性。此外，癌细胞和正常细胞之间的细胞间通讯是否在 肿瘤微环境对疾病复发的影响尚不清楚。使用散装系统药理学和 单细胞系统生物学方法，我们发现白血病异质性与T细胞 成熟和药物敏感性。因此，我们假设，通过靶向信号传导的克隆治疗， 由T细胞分化产生的克隆亚群中的网络将使复发性/难治性疾病最小化， 改善pT-ALL结局。我们在圣裘德的团队具有独特的优势来应对这些挑战， 在系统生物学、所有药物基因组学和T细胞发育方面拥有丰富的专业知识。具体来说，在这 我们将确定T细胞的发育如何影响pT-ALL的白血病内异质性 (Aim 1）。我们将通过对原始样本的单细胞分析，将pT-ALL中的克隆定位到T细胞成熟阶段 和正常发育的T细胞我们将确定驱动克隆异质性的克隆特异性隐藏驱动因素 和药物敏感性。接下来，我们将确定针对多个克隆中的信号驱动的药物组合 (Aim 2）。我们将整合散装系统药理学与单细胞隐藏驱动程序分析， 预测协同药物组合并通过药物筛选验证它们。我们将使用患者来源的 保留克隆复杂性的异种移植物用于体内验证。我们还将研究TME如何重新编程 在pT-ALL中用治疗调节克隆选择（目的3）。我们会重建肿瘤和TME 从scRNA-seq数据的通信网络，并阐明克隆选择的分子机制， pT-ALL治疗。总的来说，这个项目将解决内部基本的悬而未决的问题， 白血病克隆性，并提供一种新克隆治疗方法，其消除多个克隆，包括那些 从而改善T-ALL患儿的预后。

项目成果

NetBID2 provides comprehensive hidden driver analysis.

• DOI: 10.1038/s41467-023-38335-6
• 发表时间: 2023-05-04
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Dong, Xinran;Ding, Liang;Thrasher, Andrew;Wang, Xinge;Liu, Jingjing;Pan, Qingfei;Rash, Jordan;Dhungana, Yogesh;Yang, Xu;Risch, Isabel;Li, Yuxin;Yan, Lei;Rusch, Michael;McLeod, Clay;Yan, Koon-Kiu;Peng, Junmin;Chi, Hongbo;Zhang, Jinghui;Yu, Jiyang
• 通讯作者: Yu, Jiyang

scMINER: a mutual information-based framework for identifying hidden drivers from single-cell omics data.

scMINER：一种基于相互信息的框架，用于从单细胞组学数据中识别隐藏的驱动因素。

• DOI: 10.1101/2023.01.26.523391
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ding,Liang;Shi,Hao;Qian,Chenxi;Burdyshaw,Chad;Veloso,JoaoPedro;Khatamian,Alireza;Pan,Qingfei;Dhungana,Yogesh;Xie,Zhen;Risch,Isabel;Yang,Xu;Huang,Xin;Yan,Lei;Rusch,Michael;Brewer,Michael;Yan,Koon-Kiu;Chi,Hongbo;Yu,Jiyang
• 通讯作者: Yu,Jiyang