Determining the Role of Metabolism in Resistance in Acute Myeloid Leukemia

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 DESCRIPTION (provided by applicant): Altered metabolism plays a central role in malignancy and has recently been named an emerging hallmark of cancer. Acute myeloid leukemia (AML) utilizes altered metabolism to maximize cell growth and survival. The interest in cancer cell metabolism has led to the development of novel therapies that target metabolic pathways. CPI-613 is a novel agent that targets the TCA cycle currently under development for the treatment of AML. How AML cells alter their metabolic pathways in response to chemotherapy or metabolically targeted agents like CPI-613 is not currently known. We hypothesize that AML cells following treatment with chemotherapy will up-regulate energy generation through the TCA cycle, glycolysis and autophagy and further that inhibition of one of these pathways will shift energy production to the other two. The aims of this proposal are 1) determine the role of the master metabolic regulator AMPK in response to inhibition of the TCA cycle with the novel agent CPI-613, 2) determine the contribution of glycolysis and autophagy as alternative energy pathways when the TCA cycle is inhibited and 3) determine the changes in AML cell metabolism in response to standard chemotherapy agents. The results from this study will 1) uncover the role of AMPK in coordinating energy production following inhibition of the TCA cycle, 2) establish the role of glycolysis and autophagy as escape pathways for energy generation when the TCA cycle is inhibited and 3) demonstrate that AML cells up-regulate TCA cycle activity, glycolysis and autophagy following treatment with chemotherapy. These results have direct clinical implications. The TCA cycle inhibitor CPI-613 is under clinical development, the autophagy inhibitor chloroquine is FDA approved and the glycolysis inhibitor 2-deoxyglucose is under development. The proposed studies will assist in the development of novel treatment strategies for AML.