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

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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.