Defining and leveraging nutritional and circadian dependencies to augment acute leukemia therapy

定义和利用营养和昼夜节律依赖性来增强急性白血病治疗

• 批准号: 10231241
• 负责人: Joya Chandra
• 金额: $ 19.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231241
• 关键词: ARNTL gene; Acute Myelocytic Leukemia; Acute leukemia; Adipocytes; Adult; Anthracycline; Antiinflammatory Effect; Biological Markers; Blood Circulation; Cell Death; Child; Childhood Acute Myeloid Leukemia; Chronotherapy; Clinical; Consumption; Cytarabine; Data; Dendritic Cells; Dependence; Development; Diet; Diet Modification; Dietary Administration; Dietary Intervention; Dietary Sucrose; Disease; Diurnal Rhythm; Doxorubicin; Epigenetic Process; Face; Fasting; Fatty acid glycerol esters; Gene Expression; Genes; Goals; Growth; Hematopoietic Neoplasms; Heterogeneity; In Vitro; Inferior; Intervention; Lead; Link; Malignant Neoplasms; Modality; Molecular; Mus; Mutation; Nutrient; Nutritional; Nutritional status; Obesity; Outcome; Overweight; Oxidation-Reduction; Oxidative Stress; Patient-Focused Outcomes; Patients; Peripheral; Pharmacology; Prognosis; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Regimen; Relapse; Research; Retrospective Studies; Role; Stratification; Sucrose; Survival Rate; Testing; Tissues; Transcription Coactivator; Treatment Efficacy; Treatment Protocols; Treatment-related toxicity; Unhealthy Diet; United States; Vascular Endothelial Growth Factor Receptor-1; Weight; Weight Gain; Xenograft procedure; acute myeloid leukemia cell; cancer cell; cancer type; cell growth; chemotherapy; circadian; circadian pacemaker; clinically relevant; comparative efficacy; design; effective intervention; energy balance; experimental study; feeding; fetal liver kinase-2; improved; improved outcome; in vivo; kinase inhibitor; leukemia; leukemia treatment; leukemic stem cell; macrophage; modifiable behavior; molecular clock; mouse model; novel; nucleoside analog; pre-clinical; response; stem; stem cell survival; sugar; targeted treatment; treatment effect; treatment planning; tumor; tumor growth; tumor progression

PROJECT SUMMARY Nearly 11,000 adults and children are projected to die in the United States in 2019 due to acute myeloid leukemia (AML), a genetically heterogeneous blood cancer. Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, such as an internal tandem duplication (FLT3-ITD) occur in roughly 25% of patients, and constitute the most commonly seen genetic alteration in this disease. Patients who are FLT3-ITD positive face poor prognosis relative to other AML patients despite the development and clinical use of targeted therapies such as kinase inhibitors. Weight status (overweight and obesity) and poor nutritional status have also been correlated with inferior patient outcome, increased treatment-related toxicities, and an increase in abandonment of therapy. Diet quality has not been well studied as a determinant of these poor outcomes in AML. Using orthotopic xenograft mouse models for FLT3-ITD AML, we find that leukemia burden is reduced when anthracycline therapy is combined with a low fat/low sugar diet. An understudied aspect of diet is its timing and its impact on the internal circadian clock, disruption of which has been linked to cancer. Recent data has implicated proteins that control circadian clock in survival of acute myelogenous leukemia cells, as being essential for leukemia stem cell survival. In particular, the BMAL1 protein is required for AML cell growth, but its modulation has not been studied in the context of chemotherapies routinely used for leukemia treatment. We hypothesize that focused and specifically timed dietary interventions can improve chemotherapy efficacy. This represents a relatively inexpensive intervention that can be implemented globally provided the interventions are defined, implementation is feasible and there are biomarkers to follow to assess whether the interventions are having an impact. Using mouse models for leukemia to deliver these specific interventions in the setting of AML treatment, and assessing molecular changes will provide the needed preclinical data to justify inclusion of energy balance interventions into the treatment plan and inform the design of effective interventions in patients. Low fat or low sugar diets have been shown to have anti-inflammatory effects, which may be linked to reduced oxidative stress through gene expression and epigenetic mechanisms. Indeed, we find that redox modulation and macrophage/dendritic cell ratio are altered by dietary sucrose. We will further define these changes in the context of augmentation of AML therapy and as biomarkers for alterations in energy balance through the treatment continuum. In addition, we will implement restricted feeding paradigms, which are shown to alter circadian clock activity, to determine whether the quality and timing of nutritional impact influences the effects of treatment on AML. We will: Aim 1: Identify diet regimens that enhance therapy efficacy in AML FLT3-ITD bearing mouse models. Aim 2: Determine whether specific chrononutritional approaches are capable of augmenting treatment of AML. We expect our findings will lead to a potentially feasible and translatable intervention to improve treatment for a subset of AML patients with particularly poor outcomes.

项目概要 预计 2019 年美国将有近 11,000 名成人和儿童死于急性髓系白血病 白血病（AML），一种遗传异质性血癌。 FMS 样酪氨酸激酶 3 (FLT3) 突变 基因，例如内部串联重复 (FLT3-ITD) 发生在大约 25% 的患者中，并构成了 这种疾病中最常见的基因改变。 FLT3-ITD 阳性患者面临贫困 尽管已经开发和临床使用了靶向治疗，例如 激酶抑制剂。体重状况（超重和肥胖）与营养状况不佳也存在相关性 患者预后较差、治疗相关毒性增加以及放弃治疗的增加 治疗。饮食质量作为 AML 不良结局的决定因素尚未得到充分研究。使用 FLT3-ITD AML的原位异种移植小鼠模型，我们发现当 蒽环类药物治疗与低脂/低糖饮食相结合。饮食的一个未被充分研究的方面是它 时间及其对内部生物钟的影响，生物钟的破坏与癌症有关。 最近的数据表明控制生物钟的蛋白质与急性髓性白血病的生存有关 细胞，对于白血病干细胞的生存至关重要。特别是，BMAL1 蛋白是 AML 所必需的 细胞生长，但其调节尚未在常规用于化疗的背景下进行研究 白血病治疗。我们假设有针对性和特定时间的饮食干预可以 提高化疗疗效。这是一种相对便宜的干预措施，可以 在全球范围内实施，前提是干预措施已明确、实施可行且有 遵循生物标志物来评估干预措施是否产生影响。 使用白血病小鼠模型在 AML 环境中提供这些特定干预措施 治疗和评估分子变化将提供所需的临床前数据来证明纳入的合理性 将能量平衡干预纳入治疗计划，并为有效干预措施的设计提供信息 患者。低脂肪或低糖饮食已被证明具有抗炎作用，这可能与 通过基因表达和表观遗传机制减少氧化应激。事实上，我们发现氧化还原 膳食蔗糖会改变调节和巨噬细胞/树突细胞比例。我们将进一步定义这些 AML治疗增强背景下的变化以及作为能量平衡改变的生物标志物 通过治疗连续体。此外，我们将实施限制性喂养范例，如图所示 改变生物钟活动，确定营养影响的质量和时间是否会影响 治疗对 AML 的影响。我们将： 目标 1：确定可增强 AML FLT3-ITD 小鼠模型治疗效果的饮食方案。 目标 2：确定特定的时间营养方法是否能够增强 AML 的治疗。 我们期望我们的研究结果将带来潜在可行且可转化的干预措施，以改善治疗 对于一部分预后特别差的 AML 患者。