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.

项目摘要/摘要 标题：确定具有亚临床神经认知能力下降和氧化易感性的儿童 所有人的治疗早期损害 该建议是对挑衅性问题7的回应：“如何开发和使用预测模型 识别患有治疗相关并发症风险最高的患者吗？”我们先前已经确定了遗传 变体与氧化应激的差异性，与下等于下的认知功能相关。 急性淋巴细胞白血病的治疗（全部）。为临床试验准备是否抗氧化剂 治疗可以预防治疗引起的神经认知能力下降，我们将检验白血病的假设 治疗诱导氧化损伤和易感人群可测量的神经认知下降 在所有治疗的头几个月中。因此，提出的预测模型将确定患者 在主动干预可能会阻止永久治疗引起的认知的时候，童年 缺陷。我们将在三个相关的特定目的中检验这一假设：（1）前瞻性证明 亚临床治疗引起的认知功能的变化可以在前三个月内检测到 所有人的治疗和预测功能障碍后1年接受DANA治疗的儿童接受治疗 Farber癌症研究所所有财团方案16-001在美国和加拿大的八个地点； （2） 前瞻性证明治疗引起的神经认知功能变化与 基因中的靶向多态性会导致对氧化物胁迫的敏感性。 （3）前瞻性识别 基因变异与生物标志物的变化之间的关系，指示氧化损伤 中枢神经系统。神经认知功能将使用验证良好的基于​​计算机的评估 在两年的治疗期间和完成后一年 治疗，可以检测基线的神经认知能力的亚临床变化。潜在类 混合建模将用于解决随着时间的推移的不同性能变化模式，以及 在治疗的头几个月中，基线的变化将与定义幸存者的持续存在有关 完成治疗后一年多。因此，该项目将确定治疗患者 - 当干预可能阻止的治疗点，神经认知功能的相关变化（AIM 1） 进一步下降。此外，该项目完成了我们实验室的努力，以了解病理生理学 通过测试与氧化有关的基因中变体之间的关系，通过测试与治疗相关的认知下降 压力和认知能力下降（AIM 2）和氧化损伤的生物标志物（AIM 3）。那是获得的结果 预计该提案将产生积极的影响，因为它们将为改进的基础提供基础 癌症治疗的治疗指数，并有可能指导针对保护性干预措施的临床试验 减少白血病治疗治疗的永久性燃烧。