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.

项目摘要/摘要 用T细胞淋巴细胞白血病（T-All）和T细胞淋巴细胞的儿童和年轻人治疗 淋巴瘤（T-LL）随着时间的流逝而统一，因为T-LL患者在T-LL的患者中具有较高的结果 治疗。最近完成的儿童肿瘤学组（COG）3阶段临床试验AALL1231，但是 发现当T-LL而不是T-ALL患者的无事件生存率（EFS）和总体生存率（OS）提高了 仅将蛋白酶体抑制剂硼替佐米和细胞毒性化学疗法与化学疗法随机分配。在 此外，在AALL1231上启发了皮质类固醇，以消除大多数儿童的预防性颅辐射。 T-ALL患者受益于皮质类固醇强化，而T-LL患者则没有。该试验改变了 T-ALL和T-LL的处理范式，至关重要，我们确定差异的机制 对治疗的反应。对于T -ALL患者，我们在R01CA1CA193776下进行了全面的 - 摩尼克分析 以及相关的Gabriella Miller Kids First X01奖（X01HD100702）。这些研究包括蛋白质组学 对250多名T-ALL和全基因组，整个外显子组和RNA测序的儿童进行分析（WGS，WES， RNASEQ）在1250多名T-All的儿童上。我们还在 从30个T案例中的骨髓来了解克隆建筑和微环境。我们现在有 从250多名T-LL儿童中获得组织，我们将用来测试我们的中心假设 蛋白质组学，转录组和基因组特征可以：（1）识别具有较高T-all和T-LL的患者 复发的风险，（2）定义患者从新疗法中受益的可能性较高，并且（3）划定 内在（肿瘤）和外在（微环境）生物学差异，导致对差异的反应 治疗。我们将利用和扩展我们现有的T-ALL数据，并在T-LL中生成新数据以测试我们的 以下特定目的的假设。我们将执行批量基因组，转录组和蛋白质组学分析 在T-LL组织上，以及T-LL骨髓和T-ALL和T-LL CSF上的单细胞分析，并比较 T-ALL和T-LL中的肿瘤和微环境，以鉴定两者之间的生物学差异（AIM 1）。我们将 执行转录组和蛋白质组分析，以定义灵敏度和抗性机制 皮质类固醇（AIM 2）和蛋白酶体抑制剂（AIM 3）在T-ALL和T-LL中以及靶向失调蛋白 用小分子抑制剂和CRISPR-CAS9驱动抗性，以克服耐药性。 影响：我们在从儿童收集的样本和 在多中心3期试验中接受T-ALL和T-LL治疗的年轻人。我们将提高对t-的理解 全部和T-LL生物学并定义内在（癌细胞）和外部（微环境）生物学因素 区分两个。我们将确定哪些T-ALL和T-LL患者应接受蛋白酶体抑制剂和 加强皮质类固醇作为标准疗法，并确定下一代临床试验的新靶标。