Investigating cancer metabolism and its potential for therapeutic intervention

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Project Summary Cancer cells use fuels, such as glucose and glutamine, in a different way than normal cells. Indeed, this altered metabolism is the basis for several prognostic tools and treatment strategies. The idea being, that if we can understand these differences, than we can exploit them to be able to discriminate between a cancer cell and normal cell, providing specificity for therapeutic intervention. Otto Warburg discovered, over a century ago, that cancer cells prefer to convert glucose to lactate even in the presence of oxygen, later coined ‘aerobic’ glycolysis. His hypothesis has been modified to include the importance of the TCA cycle as well as glycolysis as a means of creating biosynthetic building blocks, such and lipids and nucleic acids. The TCA cycle integrates glucose, amino acid and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. If we can understand how cancer cells regulate these processes, perhaps we can identify new targets for intervention. This proposal has two main goals. The first focuses on understanding the role of altered metabolism in cancer and identifying new targets for therapy. The second is on my career development from graduate student, to post doctoral associate and my ultimate goal of becoming a successful independent cancer researcher. My first aim is the foundation of my dissertation project which focuses on phosphoenolpyruvate carboxykinase (PEPCK), an enzyme is well known for its role in gluconeogenesis. Previous studies also show PEPCK is a key regulator of TCA cycle flux. Our lab has demonstrated a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation. Aim 2 proposes to expand on these studies to a colon carcinogenesis model as well as understanding the role of PEPCK’s subcellular localization in metabolism and growth. Finally, Aim 3 proposes how I will expand upon my pre-doctoral training in order to become a successful cancer research focusing on cancer metabolism. By completing these aims, I am confident that with this training mechanism I will be able to become an independent cancer researcher.