Determining the Role of Metabolism in Resistance in Acute Myeloid Leukemia

 描述(申请人提供)：新陈代谢改变在恶性肿瘤中起着核心作用，最近被命名为癌症的一个新的标志。急性髓系白血病(AML)利用改变的新陈代谢来最大化细胞生长和存活。对癌细胞代谢的兴趣导致了针对代谢途径的新疗法的发展。CPI-613是一种针对目前正在开发的治疗AML的TCA周期的新型药物。目前尚不清楚AML细胞如何在化疗或代谢靶向药物如CPI-613的作用下改变其代谢途径。我们假设，化疗后的AML细胞将通过TCA循环、糖酵解和自噬上调能量产生，进一步抑制其中一条途径将把能量产生转移到另外两条途径。这项建议的目的是1)确定主代谢调节因子AMPK在新药CPI-613抑制TCA周期中的作用，2)确定糖酵解和自噬作为替代能量途径在TCA周期被抑制时的作用，以及3)确定AML细胞代谢对标准化疗药物的响应变化。这项研究的结果将1)揭示AMPK在抑制TCA循环后协调能量产生的作用，2)确定糖酵解和自噬作为TCA循环被抑制时能量产生的逃逸途径的作用，3)证明AML细胞在化疗后上调TCA循环活性、糖酵解和自噬。这些结果具有直接的临床意义。TCA循环抑制剂CPI-613正在临床开发中，自噬抑制剂氯喹已获得FDA批准，糖酵解抑制剂2-脱氧葡萄糖正在开发中。拟议的研究将有助于开发新的急性髓细胞白血病治疗策略。

 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.