Drug Resistant Pathways in Relapsed Acute Lymphoblastic Leukemia(ALL)

复发性急性淋巴细胞白血病（ALL）的耐药途径

• 批准号: 8464532
• 负责人: William L. Carroll
• 金额: $ 40.7万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464532
• 关键词: Acquired uniparental disomy; Acute Lymphocytic Leukemia; Biological; Biological Assay; Blast Cell; Bone Marrow; Cell Line; Cells; Cessation of life; Characteristics; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Children' s Oncology Group; Diagnosis; Disease; Disease Pathway; Disease Resistance; Disease remission; Dissection; Drug resistance; Drug resistance pathway; Enrollment; Epigenetic Process; Event; Evolution; Extramedullary; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Immunophenotyping; In Vitro; Inferior; Knowledge; Lead; Lesion; Link; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Microarray Analysis; Molecular Genetics; Newly Diagnosed; Newly Diagnosed Disease; Non-accidental; Oligonucleotide Microarrays; Outcome; Pathway interactions; Patients; Population; Prognostic Factor; Protocols documentation; Recurrence; Recurrent disease; Relapse; Residual state; Resistance; Role; Sampling; Single Nucleotide Polymorphism Map; Site; Small Interfering RNA; Stem cell transplant; Techniques; Testing; Therapeutic; Time; Transcript; Treatment Failure; chemotherapeutic agent; chemotherapy; cohort; density; design; drug sensitivity; early experience; experience; human PTTG1 protein; improved; leukemia; novel therapeutic intervention; outcome forecast; pre-clinical; public health relevance; research study; success; survivin; therapeutic target

DESCRIPTION (provided by applicant): In spite of dramatic improvements in cure rate for the most common childhood malignancy, acute lymphoblastic leukemia (ALL), one in four to five children will suffer disease reoccurrence and their prognosis is dismal. In fact relapsed ALL is the most common cause of non-accidental death in childhood. Attempts to improve relapse outcome by intensifying chemotherapy including the use of stem cell transplantation have failed to cure the majority of children. While many prognostic factors can be used to stratify therapy, only immunophenotype (T-ALL inferior prognosis), site of relapse (bone marrow inferior to isolated extramedullary) and timing of relapse (early relapse defined as < 36 months from initial diagnosis inferior compared to late relapse) are predictive of salvage. To discover the underlying pathways that mediate drug resistance in childhood ALL we have used high throughput genomic techniques to analyze differences in global gene expression and copy number abnormalities (CNAs) in matched diagnosis-relapse paired samples from children enrolled on Children's Oncology Group (COG) protocols. Our early results indicate that most cases of early relapse are characterized by a proliferative gene signature and we suggest that these clones exist at diagnosis. In contrast, we hypothesize that many cases of late relapse occur through acquisition of additional genetic and/or epigenetic changes. Importantly, we have identified attractive targets for novel therapeutic approaches including a subset that have been validated in preclinical assays. The goals of this application are to extend these observations and confirm our hypothesis through the following specific aims: 1) discover biological pathways responsible for the emergence of resistant disease by identifying gene signatures associated with early and late relapse using oligonucleotide arrays, 2) to determine the critical lesions that drive resistance by identifying CNAs unique to the relapsed clone using Affymetrix 6.0 SNP arrays, 3) to validate the critical roles of the pathways identified in aims 1 and 2 by modulating expression in a panel of ALL cell lines exposed to chemotherapy and to establish whether transcript levels correlate with the drug sensitivity of blasts exposed ex vivo to agents used in ALL treatment, and 4) to formally test our hypothesis by documenting the evolution of gene expression signatures in residual blasts at end induction, and by "backtracking" relapse specific deletions to determine if relapsed clones were present at diagnosis before the application of therapy. The results of these studies will lead to an understanding of the cellular origin of relapsed disease and the pathways that are responsible for treatment failure. Such information will lead to the discovery of pathways that can be targeted in future trials.

描述（由申请人提供）：尽管最常见的儿童恶性肿瘤，急性淋巴细胞性白血病（全部）的治愈率有了显着改善，但四分之一至五分之五的儿童将遭受疾病的再发生，预后很沮丧。实际上，一切复发是童年时期非事故死亡的最常见原因。通过加强化学疗法（包括使用干细胞移植）来改善复发结果的尝试无法治愈大多数儿童。尽管许多预后因素可用于分层治疗，但仅免疫表型（T-All Predior预后），复发部位（骨髓不足于孤立的外尿外）和复发的时间（与晚期复发相比初始诊断较低诊断为<36个月的早期复发定义为<36个月）。为了发现介导童年中耐药性的潜在途径，我们使用了高通量基因组技术来分析来自纳入儿童肿瘤组（COG）方案的儿童的匹配诊断 - 造影配对样品中全球基因表达和拷贝数异常（CNA）的差异。我们的早期结果表明，大多数早期复发病例的特征是增生基因的特征，我们建议这些克隆存在于诊断中。相比之下，我们假设许多晚期复发的病例是通过获取其他遗传和/或表观遗传学变化而发生的。重要的是，我们已经确定了新型治疗方法的有吸引力的靶标，包括在临床前测定中已验证的子集。 The goals of this application are to extend these observations and confirm our hypothesis through the following specific aims: 1) discover biological pathways responsible for the emergence of resistant disease by identifying gene signatures associated with early and late relapse using oligonucleotide arrays, 2) to determine the critical lesions that drive resistance by identifying CNAs unique to the relapsed clone using Affymetrix 6.0 SNP arrays, 3) to validate the critical roles of the在目标1和2中鉴定的途径通过调节暴露于化学疗法的所有细胞系中的表达，并确定转录水平是否与所有治疗中使用的爆炸的药物敏感性相关在应用治疗之前诊断出现。这些研究的结果将导致对复发性疾病的细胞起源以及导致治疗失败的途径的理解。这些信息将导致发现可以在以后的试验中针对的途径。