Biomarkers of dasatinib response and resistance in T-cell acute lymphoblastic leukemia

T 细胞急性淋巴细胞白血病达沙替尼反应和耐药的生物标志物

• 批准号: 10438869
• 负责人: David T. Teachey
• 金额: $ 58.72万
• 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: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438869
• 关键词: ABL1 gene; Accounting; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Algorithms; B-Cell Acute Lymphoblastic Leukemia; BCL-2 Protein; BCL2 gene; Biological Markers; Biology; CRISPR screen; Cells; Characteristics; Child; Childhood; Childhood Leukemia; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Combination Drug Therapy; Combined Modality Therapy; Coupling; Cytotoxic Chemotherapy; Cytotoxic agent; Dasatinib; Data; Data Set; Dependence; Development; Drug resistance; Exhibits; Gene Expression Profile; Gene Expression Profiling; Genes; Genomics; Heterogeneity; Inferior; Knowledge; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Malignant Childhood Neoplasm; Malignant Neoplasms; Medicine; Modeling; Molecular; Patients; Pediatric Oncology Group; Pharmaceutical Preparations; Phenotype; Phosphoproteins; Phosphorylation; Quality of life; Refractory; Relapse; Reporting; Research Personnel; Resistance; Resources; Role; Series; Signal Pathway; Signal Transduction; Survival Rate; Systems Biology; Testing; Therapeutic; Tissue-Specific Gene Expression; Toxic effect; Tyrosine Kinase Inhibitor; Up-Regulation; Validation; Variant; Work; antagonist; base; biomarker performance; biomarker-driven; cancer cell; chemotherapy; clinically translatable; cohort; conventional therapy; cytotoxicity; drug testing; experience; fighting; gene network; genome-wide; genomic data; high risk; improved; in vivo; inhibitor; innovation; insight; leukemia; next generation; novel; novel therapeutics; patient derived xenograft model; patient population; personalized cancer therapy; resistance gene; response; side effect; single-cell RNA sequencing; therapeutic target; transcriptome sequencing; treatment response; whole genome

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children, with T-cell ALL accounting for 15% of cases. T-ALL in children is associated with aggressive clinical features and inferior treatment response to combination chemotherapy, compared to B-cell ALL. Further intensification of cytotoxic drug-based therapy is ineffective for relapsed T-ALL and novel agents are much needed for these patients. We recently discovered that a significant proportion of pediatric T-ALL exhibits exceptional response to tyrosine kinase inhibitor dasatinib, in an ABL-independent fashion. Our preliminary genomic analyses pointed to the activation of the preTCR-LCK signaling pathway as a potential driver of this drug response phenotype. We have developed an innovative systems biology approach that integrates transcriptional profile with functional ex vivo drug testing in order to develop a clinically translatable biomarker for sensitivity and resistance to dasatinib in T-ALL. We hypothesize that our systems biology approach can comprehensively identify molecular determinants of dasatinib response in T-ALL, and that dasatinib-sensitive T-ALLs have distinct clinical and genomic features. In this project, we propose to 1) develop a systems biology-based biomarker model of dasatinib sensitivity in T- ALL; 2) systematically characterize genomics and clinical features associated with dasatinib sensitivity in T-ALL, and 3) explore mechanism of dasatinib resistance in T-ALL and develop biomarker-driven combination therapy to overcome drug resistance. Successful completion of these studies is likely to substantially shift the paradigm of how pediatric T-ALL is treated and significantly impact the next generation of clinical trials and improve cure rates for children with this devastating illness.

抽象的 急性淋巴细胞白血病（ALL）是儿童最常见的癌症，其中T细胞ALL占15% 案例。儿童 T-ALL 与侵袭性临床特征和较差的治疗反应有关 联合化疗，与 B 细胞 ALL 相比。进一步强化以细胞毒性药物为基础的治疗 对于复发性 T-ALL 无效，这些患者非常需要新的药物。我们最近发现 很大一部分儿童 T-ALL 对酪氨酸激酶抑制剂达沙替尼表现出异常反应， 以独立于 ABL 的方式。我们的初步基因组分析表明 preTCR-LCK 被激活 信号通路作为这种药物反应表型的潜在驱动因素。我们开发了一种创新的 系统生物学方法，将转录谱与功能性离体药物测试相结合，以便 开发一种临床可转化的生物标志物，用于检测 T-ALL 患者对达沙替尼的敏感性和耐药性。我们假设 我们的系统生物学方法可以全面识别达沙替尼反应的分子决定因素 达沙替尼敏感的 T-ALL 具有独特的临床和基因组特征。 在这个项目中，我们建议 1) 开发一种基于系统生物学的达沙替尼敏感性生物标志物模型 全部; 2) 系统地表征 T-ALL 中与达沙替尼敏感性相关的基因组学和临床特征， 3）探索T-ALL达沙替尼耐药机制并开发生物标志物驱动的联合疗法 以克服耐药性。 这些研究的成功完成可能会大大改变儿科 T-ALL 的治疗模式 治疗并对下一代临床试验产生重大影响，并提高患有此病的儿童的治愈率 毁灭性的疾病。