(625m) Effects of Small-Molecule Inhibition of Central Metabolism In a B-Cell Lymphoma Model of Myc-Driven Cancer

Cancer metabolism has, in recent years, become an attractive avenue for targeted therapeutics. Anabolic and catabolic processes are tightly regulated within any proliferating cell, with a cancerous cell being no different. Central metabolism supplies the cell with intermediate metabolites that satisfy energy, redox homeostasis, and biosynthetic requirements. The overall metabolic state is determined by the oncogenic mutations and microenvironmental conditions that characterize a particular cancer cell. The transcription factor c-Myc is an oncoprotein that exhibits deregulated expression in over 30% of all cancers. In addition to its role as a global regulator of cell cycle and apoptosis, c-Myc exerts significant control over cellular metabolism. Targeting deregulated metabolic pathways with small-molecule inhibitors has become an attractive therapeutic strategy because of recent findings that suggest these metabolic alterations may play a critical role in promoting cancer progression.

Our recent work using a B-cell line with regulatable expression of c-Myc reveals a strong coupling between c-Myc expression and metabolic state. We applied metabolic flux analysis (MFA) using ¹³C-labeled glucose tracers and GC-MS profiling to compare High and Low Myc states. Growth was inhibited by 50% under the Low Myc state, while specific rates of glucose uptake and lactate secretion were decreased by 20% and uptake of several amino acids such as glutamine and serine were decreased by over 50% in comparison to the High Myc state. We have also treated High and Low Myc expressing cells with selective metabolic inhibitors to determine their effects on growth and metabolism. We hypothesized that the High Myc cells would be more sensitive to these inhibitors than the Low Myc cells. Early results indicate that High Myc cells are more sensitive to oxamate, which is a specific inhibitor of lactate dehydrogenase, with an IC50 an order of magnitude lower than that of the Low Myc cells. Ongoing work is being conducted to quantify the metabolic alterations that occur in response to this and other metabolic inhibitors using ¹³C-MFA, and how they differ depending on the level of c-Myc expression.