Identifying children with subclinical neurocognitive decline and susceptibility to oxidative damage during the early months of therapy for ALL

识别在 ALL 治疗的最初几个月内出现亚临床神经认知衰退和易受氧化损伤的儿童

• 批准号: 10004590
• 负责人: PETER D. COLE
• 金额: $ 67.99万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004590
• 关键词: Academic achievement; Acute Lymphocytic Leukemia; Aftercare; Age; Antioxidants; Attention Concentration; Behavior Therapy; Biological Markers; Brain; Canada; Cerebrospinal Fluid; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Clinical Trials; Cognitive deficits; Complement; Computers; Dana-Farber Cancer Institute; Detection; Deterioration; Early treatment; Enzyme-Linked Immunosorbent Assay; Folic Acid; Foundations; Functional disorder; Funding; Genes; Genetic Polymorphism; High Pressure Liquid Chromatography; Impaired cognition; Impairment; Individual; Inferior; Institution; Intervention; Isoprostanes; Laboratories; Lead; Learning; Link; Malignant Childhood Neoplasm; Measurable; Measures; Memory; Modeling; Neuraxis; Neurocognitive; Neurocognitive Deficit; Occupational; Oxidative Stress; Patients; Pattern; Performance; Pharmacology; Physiology; Pre-Clinical Model; Predisposition; Preparation; Prospective Studies; Protocols documentation; Quality of life; Research; Schools; Siblings; Site; Subgroup; Survivors; Testing; Therapeutic Index; Therapeutic Trials; Time; United States; Variant; aged; antioxidant therapy; base; cancer therapy; cognitive function; curative treatments; genetic analysis; genetic variant; high risk; improved; innovation; instrument; leukemia; leukemia treatment; neurotoxicity; oxidative damage; patient subsets; predictive modeling; prevent; prospective; prospective test; response; thiobarbituric acid; treatment effect; treatment risk

Project Summary/Abstract Title: Identifying children with subclinical neurocognitive decline and susceptibility to oxidative damage during the early months of therapy for ALL This proposal is in response to Provocative Question 7, “How can prediction models be developed and used to identify patients at highest risk of treatment related complications?” We have previously identified genetic variants conferring susceptibility to oxidative stress that are associated with inferior cognitive function after treatment for acute lymphoblastic leukemia (ALL). In preparation for a clinical trial testing whether antioxidant therapy can protect against treatment-induced neurocognitive decline, we will test the hypothesis that leukemia therapy induces oxidative damage and measurable neurocognitive decline among susceptible individuals during the first months of ALL therapy. The proposed prediction model will therefore identify patients with childhood ALL at a time when a proactive intervention might prevent permanent treatment-induced cognitive deficits. We will test this hypothesis in three related Specific Aims: (1) Prospectively demonstrate that subclinical treatment-induced changes in cognitive function can be detected in the first three months of treatment for ALL and predict dysfunction 1 year after treatment among children being treated for ALL on Dana Farber Cancer Institute ALL Consortium protocol 16-001 at eight sites in the United States and Canada; (2) Prospectively demonstrate relationships between treatment-induced changes in neurocognitive functioning and targeted polymorphisms in genes conferring susceptibility to oxidative stress. and (3) Prospectively identify relationships between gene variants and changes in biomarkers indicative of oxidative damage within the central nervous system. Neurocognitive function will be assessed using a well-validated computer-based instrument (Cogstate) at multiple time points during the two years of therapy and one year after completion of treatment, allowing detection of subclinical changes in neurocognitive abilities from baseline. Latent Class Mixture Modeling will be used to resolve distinct patterns of change in performance over time, and patterns of changes from baseline during the first months of treatment will be linked to deficits persisting among survivors more than one year after completion of treatment. This project will therefore identify patients with treatment- related changes in neurocognitive function (Aim 1) at a point in therapy when an intervention might prevent further decline. In addition, the project complements our laboratory efforts to understand the pathophysiology of treatment-related cognitive decline, by testing the relationship between variants in genes related to oxidative stress and cognitive decline (Aim 2) and biomarkers of oxidative damage (Aim 3). Thus, the results obtained from this proposal are expected to have a positive impact because they will provide the foundation to improve the therapeutic index of cancer therapy, and potentially guide clinical trials of protective interventions, aimed at reducing the permanent burdens of curative treatment for leukemia.

项目总结/摘要 标题：识别亚临床神经认知功能减退和对氧化应激敏感的儿童 ALL治疗前几个月的损伤 本提案是对挑衅性问题7的回应，“如何开发和使用预测模型， 确定治疗相关并发症风险最高的患者？”我们之前已经鉴定出了 变异赋予氧化应激的易感性，与认知功能低下有关， 急性淋巴细胞白血病（ALL）的治疗。为了准备一项临床试验， 治疗可以防止治疗引起的神经认知能力下降，我们将测试白血病的假设， 治疗在易感个体中诱导氧化损伤和可测量的神经认知下降 在ALL治疗的最初几个月。因此，所提出的预测模型将识别具有以下特征的患者： 在积极干预可能防止永久性治疗诱导的认知功能障碍的时候， 赤字我们将在三个相关的具体目标中检验这一假设：（1）Proximity证明， 亚临床治疗引起的认知功能变化可以在治疗的前三个月检测到。 在接受Dana治疗的ALL儿童中，治疗ALL并预测治疗后1年的功能障碍 法伯癌症研究所ALL联盟方案16-001，在美国和加拿大的8个研究中心;（2） 普罗维登斯证实了治疗诱导的神经认知功能变化与 靶向基因多态性赋予氧化应激的易感性。（3）概率识别 基因变异与指示氧化损伤的生物标志物变化之间的关系 中枢神经系统神经认知功能将使用经过充分验证的基于计算机的 仪器（Cogstate）在两年内的治疗和一年后完成的多个时间点 治疗，允许检测神经认知能力相对于基线的亚临床变化。潜在类别 混合建模将用于解决性能随时间变化的不同模式，以及 治疗前几个月较基线的变化将与幸存者中持续存在的缺陷有关 治疗结束后一年以上。因此，该项目将确定接受治疗的患者- 在治疗过程中，当干预可能阻止神经认知功能（目标1）的相关变化时， 进一步下降。此外，该项目补充了我们的实验室努力，以了解病理生理学 治疗相关的认知能力下降，通过测试与氧化相关的基因变异之间的关系， 应激和认知能力下降（目标2）和氧化损伤的生物标志物（目标3）。因此，获得的结果 预计将产生积极的影响，因为它们将为改善 癌症治疗的治疗指数，并可能指导保护性干预措施的临床试验，旨在 减轻白血病治愈治疗的永久负担。