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（由适用提供）：对患有T细胞急性淋巴细胞淋巴细胞白血病（T-ALL）的儿童和年轻人的强化，高剂量，多药化学疗法的引入提高了事件的生存期（EFS），从15％-20％到50％-85％。尽管有这些进展，但中继T-all的预后却令人沮丧，报告的3年EFS率<15％。根据T-All治疗的主要目标是防止继电器。该果阿不可或缺的是适当的风险分层，以确定哪些患者需要更深入的治疗 或治愈的替代方法。与B-all不同，在基于MRD的风险分层中，遗传改变和MRD的组合可以准确地预测结果，在T-All遗传异常中并非独立预后。尽管MRD在T-All中的风险分层有所改善，但大多数浮雕发生在被归类为“较低”风险的患者中。尽管T-All的遗传改变存在明显的异质性，但我们组的最新数据表明，许多具有高风险T-A​​LL的患者具有有限的放松管制信号通路和细胞过程。为了满足我们的长期目标，需要增强对这些不受管制的途径的了解：改善风险分层并为高风险T-all的儿童开发新颖的目标疗法。 AALL1231是3阶段儿童肿瘤学组（COG）引起的CTEP批准的临床试验检验，该试验检验了蛋白酶体抑制剂硼替佐米型在标准T-ALL治疗中的添加将提高生存率。我们的小组在该试验的发展中发挥了重要作用，我们将领导临床试验，以及相关生物学。我们将通过对从AALL1231收集的患者样本进行详细的机械分析来提高对T-All的生化基础的理解，这将与结果数据相关。根据我们的强制初步数据，我们假设蛋白质细胞应激激活，蛋白酶体的改变和信号网络激活的模式 将确定我们可以的生物学相关的放松管制途径：（1）有效地用新型药物靶向； （2）用于开发“高风险”蛋白表达曲线，该蛋白表达曲线可以预测与MRD结合使用。我们将以以下特定目的检验我们的假设：（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，以识别和靶向与生物学相关的异常活化途径； （3）我们将确定目前被归类为诊断较低风险的患者，其预后较差，需要替代治疗，并通过改进MRD测试以及通过开发预测性高风险蛋白质表达概况来开发更准确的风险分配模式。我们预计，这些综合翻译高度机理的分析将通过改善风险分配和理性基于生物学的靶向疗法的发展而在不久的将来带来T-All的儿童的结果。