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

改善 T-ALL 儿童的风险分配并开发新疗法

• 批准号: 8862616
• 负责人: Michelle L. Hermiston
• 金额: $ 70.93万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862616
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Affect; Alternative Therapies; Biochemical; Biology; Blast Cell; Bortezomib; Cancer Therapy Evaluation Program; Cell physiology; Cells; Cellular Stress; Child; Childhood Precursor T Lymphoblastic Leukemia; Clinical; Clinical Data; Clinical Trials; Cytometry; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Disease Outcome; Disease-Free Survival; Dose; Frequencies; Future; Genetic; Goals; Growth; Heat shock proteins; Heterogeneity; Immunophenotyping; In Vitro; International; Lead; MAP Kinase Gene; Methods; Molecular; Molecular Abnormality; Molecular Profiling; Mutation; Outcome; Pathway interactions; Patient risk; Patients; Pattern; Pediatric Oncology Group; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Phenotype; Proteasome Inhibitor; Protein Analysis; Proteins; Relapse; Reporting; Residual Neoplasm; Resistance; Risk; Sampling; Scientist; Signal Pathway; Signal Transduction; Stratification; Survival Rate; T-Lymphocyte; Testing; Vertebral column; base; chemotherapy; deep sequencing; design; high risk; human FRAP1 protein; improved; in vivo Model; inhibitor/antagonist; meetings; multicatalytic endopeptidase complex; notch protein; novel; outcome forecast; prevent; progenitor; prognostic; protein expression; public health relevance; response; small molecule; stress protein; targeted treatment; therapy development; young adult

 DESCRIPTION (provided by applicant): The introduction of intensive, high-dose, multi-agent chemotherapy has improved the event free survival (EFS) for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL) from 15%-20% to 50%-85%. Despite these advances, relapsed T-ALL has a dismal prognosis with reported 3-year EFS rates of <15%. Accordingly, the primary goal in the treatment of T-ALL is to prevent relapse. Integral to this goa is appropriate risk stratification in order to determine which patients need more intensive therapy or alternative approaches for cure. Unlike B-ALL, where a combination of genetic alterations and MRD can accurately predict outcome, in T-ALL genetic abnormalities are not independently prognostic in MRD-based risk stratification. While MRD has improved risk stratification in T-ALL, the majority of relapses occur in patients classified as "lower" risk. Despite significant heterogeneity in genetic alterations in T-ALL, recent data from our group and others suggest that many patients with high risk T-ALL share a limited set of deregulated signaling pathways and cellular processes. Enhanced understanding of these deregulated pathways is needed in order to meet our long-term goal: To improve risk stratification and to develop novel targeted therapies for children with high risk T-ALL. AALL1231 is phase 3 Children's Oncology Group (COG)-initiated CTEP-approved clinical trial testing the hypothesis that the addition of the proteasome inhibitor bortezomib to standard T-ALL therapy will improve survival. Our group was instrumental in the development of that trial, and we will lead the clinical trial, as well as, perorm the correlative biology. We will improve understanding of the biochemical underpinnings of T-ALL by detailed mechanistic analysis of patient samples collected from AALL1231, which we will correlate with outcome data. Based on our strong preliminary data, we hypothesize that the pattern of protein cell stress activation, proteasome alterations, and signaling network activation will ascertain biologically relevant deregulated pathways that we can: (1) effectively target with novel agents; and (2) use to develop a "high-risk" protein expression profile that can predict outcome when combined with MRD. We will test our hypothesis with the following specific aims: (1) We will determine if changes in proteasome function or cell stress expression patterns can predict drug response and resistance in T-ALL patients treated on AALL1231; (2) We will investigate cell signaling pathways in T-ALL in order to identify and target biologically relevant abnormal activated pathways; and, (3) We will identify patients currently classified as lower risk at diagnosis that have poor outcome and need alternative therapy and use them to develop a more accurate risk allocation schema through improved MRD testing and through the development of a predictive high risk protein expression profile. We anticipate these integrative translational highly mechanistic analyses will lead to improved outcome for children with T-ALL in the near future through improved risk allocation and the development of rational biologically-based targeted therapies.

 描述（由申请人提供）：强化、高剂量、多药化疗的引入将 T 细胞急性淋巴细胞白血病 (T-ALL) 儿童和年轻人的无事件生存期 (EFS) 提高了 15%-尽管取得了这些进展，但复发性 T-ALL 的预后较差，据报道 3 年 EFS 率<15%。 T-ALL 的治疗是为了预防复发，这一目标的一个重要组成部分是适当的风险分层，以确定哪些患者需要更强化的治疗。 与 B-ALL 不同，B-ALL 中基因改变和 MRD 的结合可以准确预测结果，而 T-ALL 中的基因异常不能独立预测基于 MRD 的风险分层，而 MRD 可以改善 T-ALL 的风险分层。 ALL，大多数复发发生在“较低”风险的患者中，尽管 T-ALL 的基因改变存在显着异质性，但我们小组和其他人的最新数据表明，许多高风险 T-ALL 患者都有一组有限的放松管制。为了实现我们的长期目标，需要加强对这些信号通路和细胞过程的了解：改善风险分层并为高风险 T-ALL 儿童开发新型靶向疗法 AALL1231 处于 3 期儿童肿瘤学组。 (COG) 发起的 CTEP 批准的临床试验测试了以下假设：在标准 T-ALL 疗法中添加蛋白酶体抑制剂硼替佐米将提高生存率。我们的团队在该疗法的开发中发挥了重要作用。试验，我们将领导临床试验，并进行相关生物学研究。我们将通过对从 AALL1231 收集的患者样本进行详细的机制分析来增进对 T-ALL 生化基础的理解，并将其与结果数据相关联。基于我们强有力的初步数据，我们捕获了蛋白质细胞应激激活、蛋白酶体改变和信号网络激活的模式 将确定生物学相关的解除管制途径，我们可以：（1）用新药物有效靶向；（2）用于开发“高风险”蛋白质表达谱，与 MRD 结合时可以预测结果。具体目标如下：(1) 我们将确定蛋白酶体功能或细胞应激表达模式的变化是否可以预测接受 AALL1231 治疗的 T-ALL 患者的药物反应和耐药性；(2) 我们将研究 T-ALL 中的细胞信号通路为了识别和以生物学相关的异常激活途径为目标；(3) 我们将识别目前在诊断时被归类为低风险但结果不佳且需要替代治疗的患者，并通过改进 MRD 测试和开发来使用它们分配来开发更准确的风险模式。我们预计这些综合转化高度机械分析将在不久的将来通过改善风险和开发合理的基于生物学的靶向治疗来改善 T-ALL 分配儿童的结果。