Improving risk allocation and developing novel therapies for children with T-ALL and T-LL

改善 T-ALL 和 T-LL 儿童的风险分配并开发新疗法

• 批准号: 10585102
• 负责人: Michelle L. Hermiston
• 金额: $ 85.16万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-04 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585102
• 关键词: Acute T Cell Leukemia; Adrenal Cortex Hormones; Architecture; Automobile Driving; Award; Biological; Biological Factors; Biology; Bone Marrow; Bortezomib; CRISPR/Cas technology; Cells; Child; Clinical; Clinical Data; Clinical Trials; Cranial Irradiation; Cytotoxic Chemotherapy; Data; Data Set; Disease; Disease-Free Survival; Drug resistance; Flow Cytometry; Genes; Genome; Genomics; Glucocorticoids; Goals; International; Lymphoblastic Leukemia; Lymphoblastic lymphoma; Marrow; Outcome; Pathway interactions; Patients; Pediatric Oncology Group; Phase III Clinical Trials; Positioning Attribute; Proteasome Inhibitor; Proteins; Proteome; Proteomics; Randomized; Relapse; Resistance; Risk; Sampling; Slide; Steroid Resistance; Steroids; T-Lymphocyte; Testing; Time; Tissues; Vertebral column; arm; cancer cell; chemotherapy; cohort; comparison group; data integration; differential expression; exome sequencing; genome sequencing; genomic data; genomic profiles; heat-shock factor 1; high risk; improved; improved outcome; inhibitor; innovation; lead candidate; leukemia treatment; leukemia/lymphoma; leukemogenesis; next generation; novel; novel therapeutics; patient derived xenograft model; phase III trial; prophylactic; proteomic signature; relapse patients; relapse risk; resistance factors; response; small molecule inhibitor; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; treatment response; tumor; whole genome; young adult

Project Summary/Abstract The treatment for children and young adults with T-cell lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL) has harmonized over time as T-LL patients were shown to have superior outcomes with T-ALL therapy. The recently completed Children’s Oncology Group (COG) phase 3 clinical trial AALL1231, however, found that T-LL but not T-ALL patients had improved event-free survival (EFS) and overall survival (OS) when randomized to the proteasome inhibitor bortezomib plus cytotoxic chemotherapy vs chemotherapy alone. In addition, corticosteroids were intensified on AALL1231 to eliminate prophylactic cranial radiation in most children. T-ALL patients benefited from the corticosteroid intensification and T-LL patients did not. This trial changed the treatment paradigm for T-ALL and T-LL and it is critical we identify the mechanisms underlying the differential response to therapy. For T-ALL patients, we performed comprehensive -omic analyses under R01CA193776 and an associated Gabriella Miller Kids First X01 award (X01HD100702). These studies included proteomic profiling on over 250 children with T-ALL and whole genome, whole exome, and RNA sequencing (WGS, WES, RNAseq) on over 1250 children with T-ALL. We also performed single cell genomic profiling (scRNASeq) on bone marrow from 30 T-ALL cases to understand clonal architecture and microenvironment. We now have access to tissues from over 250 children with T-LL which we will use to test our central hypothesis that specific proteomic, transcriptomic, and genomic profiles can: (1) identify patients with T-ALL and T-LL that have a higher risk of relapsing, (2) define patients that have a higher likelihood to benefit from novel therapies, and (3) delineate intrinsic (tumor) and extrinsic (microenvironment) biologic differences that lead to the differential response to therapy. We will leverage and expand our existing T-ALL data and generate new data in T-LL to test our hypothesis with the following specific aims. We will perform bulk genomic, transcriptomic, and proteomic profiling on T-LL tissues, as well as single cell profiling on T-LL bone marrow and T-ALL and T-LL CSF and compare the tumor and microenvironment in T-ALL and T-LL to identify biologic differences between the two (Aim 1). We will perform transcriptome and proteome profiling to define mechanisms of sensitivity and resistance to corticosteroids (Aim 2) and proteasome inhibitors (Aim 3) in T-ALL and T-LL and target dysregulated proteins driving resistance with small molecule inhibitors and CRISPR-Cas9 to overcome drug resistance. Impact: We are uniquely positioned to perform highly innovative studies in samples collected from children and young adults with T-ALL and T-LL treated on multi-center phase 3 trials. We will improve understanding of T- ALL and T-LL biology and define intrinsic (cancer cell) and extrinsic (microenvironment) biologic factors that distinguish the two. We will identify which T-ALL and T-LL patients should receive proteasome inhibitors and intensified corticosteroids as standard therapy and identify novel targets for the next generation of clinical trials.

项目总结/摘要 儿童和年轻人T细胞淋巴细胞白血病（T-ALL）和T细胞淋巴细胞白血病的治疗 随着时间的推移，淋巴瘤（T-LL）患者的T-ALL结局显示出上级 疗法然而，最近完成的儿童肿瘤组（COG）3期临床试验AALL 1231， 发现T-LL而不是T-ALL患者的无事件生存期（EFS）和总生存期（OS）有所改善， 随机分为蛋白酶体抑制剂硼替佐米加细胞毒性化疗组和单纯化疗组。在 此外，在大多数儿童中，AALL 1231强化皮质类固醇以消除预防性颅辐射。 T-ALL患者受益于皮质类固醇强化，而T-LL患者则没有。这次审判改变了 T-ALL和T-LL的治疗模式，关键是我们要确定差异的潜在机制， 对治疗反应。对于T-ALL患者，我们根据R 01 CA 193776进行了全面的组学分析 以及相关的加布里埃拉米勒儿童第一X 01奖（X 01 HD 100702）。这些研究包括蛋白质组 对超过250名患有T-ALL的儿童和全基因组、全外显子组和RNA测序进行分析（WGS，WES， RNAseq）对1250多名T-ALL儿童进行了研究。我们还进行了单细胞基因组分析（scRNASeq）， 从30例T-ALL患者的骨髓中了解克隆结构和微环境。我们现在有 获取来自250多名T-LL儿童的组织，我们将使用这些组织来检验我们的中心假设， 蛋白质组学、转录组学和基因组学图谱可以：（1）鉴定具有较高的T-ALL和T-LL的患者， 复发的风险，（2）确定患者有更高的可能性受益于新的治疗，和（3）描述 内在（肿瘤）和外在（微环境）生物学差异导致对 疗法我们将利用和扩展现有的T-ALL数据，并在T-LL中生成新数据，以测试我们的 具有以下具体目标的假设。我们将进行批量基因组，转录组和蛋白质组分析 以及T-LL骨髓和T-ALL和T-LL CSF的单细胞谱，并比较 T-ALL和T-LL中的肿瘤和微环境，以确定两者之间的生物学差异（目的1）。我们将 进行转录组和蛋白质组分析，以确定敏感性和耐药机制， T-ALL和T-LL中的皮质类固醇（Aim 2）和蛋白酶体抑制剂（Aim 3）以及靶向失调蛋白 用小分子抑制剂和CRISPR-Cas9驱动耐药性以克服耐药性。 影响：我们具有独特的优势，可以对从儿童和青少年中收集的样本进行高度创新的研究， 在多中心III期试验中接受治疗的T-ALL和T-LL年轻成人。我们将提高对T- ALL和T-LL生物学并定义内在（癌细胞）和外在（微环境）生物因素， 区分两者。我们将确定哪些T-ALL和T-LL患者应该接受蛋白酶体抑制剂， 加强皮质类固醇作为标准治疗，并确定新的目标，为下一代的临床试验。