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: 10249976
• 负责人: PETER D. COLE
• 金额: $ 68.24万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249976
• 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.

项目概要/摘要 标题：识别患有亚临床神经认知衰退和氧化易感性的儿童 ALL 治疗损伤的最初几个月 该提案是对挑衅性问题 7 的回应：“如何开发预测模型并用于 识别出治疗相关并发症风险最高的患者？” 变异赋予对氧化应激的易感性，而氧化应激与认知功能较差有关 治疗急性淋巴细胞白血病（ALL） 正在准备测试是否抗氧化剂的临床试验。 治疗可以防止治疗引起的神经认知衰退，我们将检验白血病的假设 治疗会在易感个体中引起氧化损伤和可测量的神经认知能力下降 因此，所提出的预测模型将识别患有 ALL 治疗的患者。 儿童期急性淋巴细胞白血病，此时积极干预可能会预防永久性治疗引起的认知 我们将在三个相关的具体目标中检验这一假设：（1）前瞻性地证明这一点。 亚临床治疗引起的认知功能变化可以在治疗的前三个月内检测到 接受 Dana ALL 治疗的儿童接受 ALL 治疗并预测治疗后 1 年后的功能障碍 法伯癌症研究所 ALL 联盟协议 16-001，位于美国和加拿大的八个地点 (2) 前瞻性地证明治疗引起的神经认知功能变化与 基因中的目标多态性赋予氧化应激的易感性；(3) 前瞻性鉴定。 基因变异与氧化损伤生物标志物变化之间的关系 将使用经过充分验证的基于计算机的神经认知功能进行评估。 治疗两年期间和完成一年后的多个时间点的仪器（Cogstate） 治疗，允许检测神经认知能力相对于基线的亚临床变化。 混合建模将用于解决性能随时间变化的不同模式，以及 治疗头几个月相对于基线的变化将与幸存者中持续存在的缺陷有关 因此，该项目将在治疗完成一年多后确定接受治疗的患者。 在治疗中某个干预措施可能阻止神经认知功能（目标 1）发生相关变化的情况下 此外，该项目补充了我们实验室了解病理生理学的努力。 通过测试与氧化相关的基因变异之间的关系来研究与治疗相关的认知能力下降 压力和认知能力下降（目标 2）以及氧化损伤的生物标志物（目标 3）。 该提案预计将产生积极影响，因为它们将为改进提供基础 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 减轻白血病治疗的永久性负担。