Abstract Genetic studies in humans and rodents support the notion that alterations in metabolic homeostasis can directly contribute to carcinogenesis and metabolic processes may be targets for therapy. The nuclear hormone receptors (NR) control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters, and other mediators. Therefore we explored potential links between cellular metabolic control by NRs and viability of cancer cells. In this study we tested the effect of 127 NR modulators, targeting receptors known to be important in regulating metabolism or known to be viable cancer targets on the growth of different leukemic cells lines. Of the compounds tested 8, mainly targeting ER and RAR, induced significant apoptosis in these leukemias. The effects of the 8 active compounds on mitochondrial metabolism were tested in Jurkat cells and 5 compounds significantly reduced lactate levels. However, only the synthetic retinoid (CD437) significantly affected pyruvate dehydrogenase complex activity. CD437 also effected the expression of genes involved in leukemia development and therapeutic responses with the PKC pathway being the primary target. CD437 induced PKC Kinase activity and activated its downstream signals AKT and JNK. CD437 downregulated CPT-1a,and decreased the overall O2 consumption rate. Additional CD437 induced genes included those involved in the mitochondrial respiratory complex I and III and increased the production of ROS. Our results indicate that the apoptotic effect of CD437 can be linked to its regulation of mitochondrial oxidative metabolism. Citation Format: Ramy R. Attia, Jaeki Min, Rodney K. Guy. Modulating metabolic homeostasis as a therapeutic tool for leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5410. doi:10.1158/1538-7445.AM2013-5410