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

 描述(申请人提供)：采用高强度、高剂量、多药剂的化疗方法，将儿童和年轻人的T细胞急性淋巴细胞白血病(T-ALL)的无事件存活率(EFS)从15%-20%提高到50%-85%。尽管有这些进展，复发的T-ALL预后很差，据报道3年EFS率为15%。因此，T-ALL治疗的首要目标是防止复发。为了确定哪些患者需要更密集的治疗，GOA的一个组成部分是适当的风险分层 或其他治疗方法。与B-ALL不同，在B-ALL中，基因改变和MRD的组合可以准确地预测结果，而在T-ALL中，基于MRD的风险分层中，ALL基因异常并不能独立预测预后。虽然MRD改善了T-ALL的风险分层，但大多数复发发生在被归类为“较低”风险的患者。尽管T-ALL的基因改变具有显著的异质性，但来自我们小组和其他人的最新数据表明，许多高危T-ALL患者共享一组有限的信号通路和细胞过程。为了实现我们的长期目标：改善风险分层，并为高危T-ALL儿童开发新的靶向治疗方法，需要加强对这些放松管制的途径的了解。AALL1231是由儿童肿瘤学小组(COG)发起的CTEP批准的第三阶段临床试验，测试了在标准T-ALL治疗中添加蛋白酶体抑制剂Bortezomib将提高存活率的假设。我们的团队在该试验的发展中发挥了重要作用，我们将领导临床试验，以及相关生物学的研究。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生化基础的理解，我们将把这些样本与结果数据相关联。基于我们强大的初步数据，我们假设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 将确定与生物相关的解除管制的途径，我们可以：(1)用新的药物有效地靶向；以及(2)用来开发一种“高风险”的蛋白质表达谱，当与MRD结合时，可以预测结果。我们将以下列具体目标来验证我们的假设：(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，以确定并靶向生物相关的异常激活通路；以及(3)我们将识别目前被归类为低风险且预后较差且需要替代疗法的患者，并利用他们通过改进的MRD检测和开发可预测的高风险蛋白表达谱来制定更准确的风险分配方案。我们预计，通过改善风险分配和开发合理的基于生物的靶向治疗，这些综合的高度机械化的分析将在不久的将来改善T-ALL儿童的预后。

 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.