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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要由于急性髓样白血病（AML），一种遗传异质性血癌。 FMS样酪氨酸激酶3（FLT3）中的突变基因，例如内部串联重复（FLT3-ITD），大约有25％的患者，构成最常见于该疾病的遗传改变。 FLT3-ITD正面较差的患者尽管有针对性疗法的发展和临床使用，例如激酶抑制剂。体重状况（超重和肥胖）和营养状况不佳也已相关患者的结果较低，与治疗相关的毒性增加以及放弃的增加治疗。饮食质量尚未被很好地研究为AML中这些不良结果的决定因素。使用 FLT3-ITD AML的原位异种移植小鼠模型，我们发现白血病负担减轻蒽环类疗法与低脂肪/低糖饮食结合使用。饮食的一个研究是时间及其对昼夜节律内部时钟的影响，其中断与癌症有关。最近的数据暗示蛋白质控制昼夜节律时钟在急性骨髓性白血病的存活中细胞，对于白血病干细胞存活至关重要。特别是，AML需要BMAL1蛋白细胞生长，但尚未在通常用于化学疗法的背景下研究其调节白血病治疗。我们假设集中和专门定时的饮食干预措施可以提高化学疗法功效。这代表了一种相对便宜的干预措施如果定义了干预措施，实施，实施是可行的，并且有生物标志物要遵循以评估干预措施是否有影响。使用白血病的鼠标模型在AML的情况下提供这些特定的干预措施治疗和评估分子变化将提供所需的临床前数据，以证明包含能源平衡干预对治疗计划的干预，并告知有效干预措施患者。低脂肪或低糖饮食已显示出具有抗炎作用，可能会连接通过基因表达和表观遗传机制减少氧化应激。确实，我们发现氧化还原饮食蔗糖改变了调节和巨噬细胞/树突状细胞比率。我们将进一步定义这些 AML疗法增强和作为能量平衡改变的生物标志物的变化通过处理连续。此外，我们将实施受限制的喂养范例，显示改变昼夜节律的活动，以确定营养影响的质量和时机是否影响治疗对AML的影响。我们将：目标1：确定饮食方案，以增强AML FLT3-ITD轴承小鼠模型中的治疗功效。 AIM 2：确定特定的截形方法是否能够增强对AML的处理。我们希望我们的发现将导致潜在的可行和可翻译的干预措施以改善治疗对于结局特别差的AML患者的子集。