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

项目摘要 预计2019年美国将有近11，000名成人和儿童因急性骨髓性白血病而死亡。 白血病（AML），一种遗传异质性血液癌症。FMS样酪氨酸激酶3（FLT3）突变 基因，如内部串联重复（FLT3-ITD）发生在大约25%的患者中，并构成了 最常见的遗传变异FLT3-ITD阳性的患者面临贫困 尽管开发和临床使用了靶向治疗， 激酶抑制剂。体重状况（超重和肥胖）和营养状况差也有相关性 患者预后较差，治疗相关毒性增加，放弃治疗的人数增加。 疗法饮食质量作为AML不良结局的决定因素尚未得到充分研究。使用 在FLT3-ITD AML的原位异种移植小鼠模型中，我们发现， 蒽环类药物治疗与低脂/低糖饮食相结合。饮食的一个未充分研究的方面是它的 时间及其对内部生物钟的影响，破坏生物钟与癌症有关。 最近的数据表明，控制急性髓性白血病生存的昼夜节律钟的蛋白质 干细胞是白血病干细胞存活的关键。特别地，BMAL1蛋白是AML所需的。 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，有针对性的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， 在全球范围内实施，前提是干预措施得到界定，实施可行， 生物标志物，以评估干预措施是否产生影响。 使用白血病小鼠模型在AML背景下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，以证明纳入 能量平衡干预措施纳入治疗计划，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 调节和巨噬细胞/树突细胞比率被饮食蔗糖改变。我们将进一步定义这些 在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 通过连续治疗。此外，我们还将实现受限制的喂养范例，如图所示。 改变生物钟活动，以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： 目的1：确定可增强携带AML FLT 3-ITD小鼠模型治疗效果的饮食方案。 目的2：确定特定的时间营养方法是否能够加强AML的治疗。 我们希望我们的研究结果将导致一个潜在的可行和可翻译的干预，以改善治疗 对于一部分预后特别差的AML患者。

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.