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: 8257958
• 负责人: William L. Carroll
• 金额: $ 43.3万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257958
• 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. PUBLIC HEALTH RELEVANCE: Although the majority of children who are newly diagnosed with acute lymphoblastic leukemia (ALL) are now cured, recurrences develop, often unpredictably, in 25% of cases. Success in treating relapse has significantly lagged behind that of newly diagnosed disease as evidenced by the fact that only approximately one third of children with recurrent ALL survive long-term. The goal of this project is to develop a better understanding of the molecular genetic events that lead to relapse so that this knowledge can be used to identify more effective preventative and therapeutic strategies.

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白血病（ALL）的治愈率有了显着提高，但四到五名儿童中就有一人会出现疾病复发，且预后不佳。事实上，复发性 ALL 是儿童期非意外死亡的最常见原因。通过加强化疗（包括使用干细胞移植）来改善复发结果的尝试未能治愈大多数儿童。虽然许多预后因素可用于对治疗进行分层，但只有免疫表型（T-ALL 预后较差）、复发部位（骨髓优于孤立性髓外）和复发时间（早期复发定义为距初次诊断后 < 36 个月）与复发相比较差。晚期复发）是挽救的预测。为了发现介导儿童 ALL 耐药性的潜在途径，我们使用高通量基因组技术来分析来自儿童肿瘤学组 (COG) 儿童的匹配诊断-复发配对样本中整体基因表达和拷贝数异常 (CNA) 的差异协议。我们的早期结果表明，大多数早期复发病例的特征是增殖基因特征，我们建议这些克隆在诊断时就存在。相反，我们假设许多晚期复发病例是通过获得额外的遗传和/或表观遗传变化而发生的。重要的是，我们已经确定了新颖治疗方法的有吸引力的靶标，其中包括已在临床前测定中验证的子集。本申请的目标是扩展这些观察结果并通过以下具体目标证实我们的假设：1）通过使用寡核苷酸阵列识别与早期和晚期复发相关的基因特征，发现导致耐药性疾病出现的生物途径，2）确定通过使用 Affymetrix 6.0 SNP 阵列识别复发克隆特有的 CNA 来驱动耐药性的关键病变，3) 通过调节面板中的表达来验证目标 1 和 2 中确定的途径的关键作用暴露于化疗的 ALL 细胞系，并确定转录水平是否与离体暴露于 ALL 治疗中使用的药物的原始细胞的药物敏感性相关，以及 4) 通过记录残余原始细胞中基因表达特征的演变来正式检验我们的假设。结束诱导，并通过“回溯”复发特异性缺失来确定在应用治疗之前诊断时是否存在复发克隆。这些研究的结果将有助于了解复发性疾病的细胞起源以及导致治疗失败的途径。这些信息将有助于发现未来试验中的目标途径。 公共卫生相关性：虽然大多数新诊断出患有急性淋巴细胞白血病 (ALL) 的儿童现已治愈，但 25% 的病例会出现复发，而且往往是不可预测的。治疗复发的成功率明显落后于新诊断疾病的成功率，只有大约三分之一的复发性 ALL 儿童能够长期存活，这一事实证明了这一点。该项目的目标是更好地了解导致复发的分子遗传事件，以便利用这些知识来确定更有效的预防和治疗策略。