The long-term objective of this study is to identify biochemical pathways that can be used to diagnose and treat human cancers. This study will focus on central carbon metabolism, a process including the uptake and usage of glucose for energy production, cellular biosynthesis, and cell reproduction. Specifically, the work will center on cells in which the tumor suppresser PTEN is inactivated. Since PTEN is frequently inactivated in cancers, including those of the breast, prostate, ovary, endometrium and skin, the work will be relevant to a wide range of human cancers. The study seeks to test the hypothesis that inactivation of PTEN is associated with significant changes in central metabolism, and that some of these metabolic pathways may be exploited as therapeutic and prognostic targets in human cancers. Our preliminary results point to PTEN-dependent changes in metabolic flux in melanoma cells. To test this hypothesis the Specific Aims are to address the following questions using melanoma cell systems as a model: 1) What are the differences in central carbon metabolism in PTEN* and PTEN inactive tumors? 2) What metabolic pathways can be exploited as drug targets in PTEN inactive melanomas? 3) What are the effects of drugs on central metabolism in PTEN* and PTEN inactive melanoma cells? 4) Can we identify subsets of PTEN inactive tumors that are highly responsive to a metabolic blockade? The prinriary approach for the study is an analysis of carbon flux through central metabolism using 2D HSQC NMR. Flux through glycolysis, the pentose phosphate pathway, the TCA cycle, and fatty acid biosynthesis, will be quantified and compared under a number of conditions that are known to alter the function of the PTEN pathway. The studies will also define the concentrations of more then twenty key metabolites. Altogether the information gained form this work should provide an understanding how the mechanistic connections occur between PTEN/PI3K/Akt and central metabolism. It is anticipated that the work will also reveal new diagnostic and therapeutic targets.
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