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

 描述（由申请人提供）：采用强化、高剂量、多药化疗使儿童和年轻成人T细胞急性淋巴细胞白血病（T-ALL）的无事件生存率（EFS）从15%-20%提高到50%-85%。尽管有这些进展，复发性T-ALL的预后很差，据报道3年EFS率<15%。因此，T-ALL治疗的主要目标是预防复发。该果阿的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。 或其他治疗方法。与B-ALL不同，B-ALL中遗传改变和MRD的组合可以准确地预测结果，在T-ALL中，遗传异常在基于MRD的风险分层中不是独立的预后。虽然MRD改善了T-ALL的风险分层，但大多数复发发生在归类为“低”风险的患者中。尽管T-ALL的遗传变异存在显著异质性，但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失调信号通路和细胞过程。为了实现我们的长期目标，需要加强对这些失调途径的理解：改善风险分层并为高危T-ALL儿童开发新的靶向治疗。AALL 1231是3期儿童肿瘤学组（COG）发起的CTEP批准的临床试验，测试在标准T-ALL治疗中加入蛋白酶体抑制剂硼替佐米将改善生存率的假设。我们的团队在该试验的开发中发挥了重要作用，我们将领导临床试验，以及相关的生物学。我们将通过对从AALL 1231中收集的患者样本进行详细的机制分析来提高对T-ALL生化基础的理解，我们将其与结果数据相关联。基于我们强有力的初步数据，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 将确定生物学相关的去调控途径，我们可以：（1）有效地与新的药物靶向;和（2）用于开发一个“高风险”的蛋白质表达谱，可以预测结果时，结合MRD。我们将通过以下具体目标来检验我们的假设：（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接受AALL 1231治疗的T-ALL患者的药物应答和耐药性;（2）我们将研究T-ALL中的细胞信号传导通路，以识别和靶向生物学相关的异常活化通路;以及，（3）我们将确定目前诊断时被归类为低风险的患者，这些患者预后不良，需要替代治疗，并通过改进MRD检测和开发预测性高风险蛋白表达谱来开发更准确的风险分配方案。我们预计，这些综合性的翻译高度机制分析将通过改善风险分配和开发合理的基于生物学的靶向治疗，在不久的将来改善T-ALL儿童的结局。

 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.