There is a pressing need for improved therapies for many types of cancer. Here we propose to investigate cancer metabolism as a target for therapy. Many types of cancer exhibit the Warburg effect, taking up large quantities of glucose and metabolizing it into lactate rather than oxidizing it in the Krebs cycle. The Warburg effect may confer a survival advantage on cancer cells. By inhibiting specific enzymes that are involved in lactate production, it may be possible to reverse the Warburg effect and thereby selectively harm cancer cells. We will study several drugs that accomplish this by inhibiting lactate dehydrogenase or by up-regulating the activity of pyruvate dehydrogenase. A second major focus of the work is the use of hyperpolarized 13C NMR of pyruvate and its metabolites to non-invasively monitor tumor metabolism. Hyperpolarized NMR will be employed to assess the effects of different interventions, and to design a combination of drugs that brings about a maximal reversal of the Warburg effect. We will investigate the utility of hyperpolarized NMR as a technique for assessing the 'on-target'effects of various metabolic interventions, and determine whether shifts in metabolism measured with hyperpolarization can provide an early predictor of tumor response to therapy. In addition, we will investigate the use of metabolic therapies in conjunction with cisplatin, and compare the utility of hyperpolarized NMR and FDG PET in assessing tumor response.
This work is centered on the development of new therapies for cancer and new techniques for determining whether a patient's disease is responding to treatment. We will test new drugs that shut down metabolic pathways that cancer cells rely upon in an effort to selectively harm tumor cels without negatively impacting normal tissue. We will use a new technology, hyperpolarized MRI, to monitor tumor metabolism non-invasively and assess the tumor's response to therapy.
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|Hu, Hai; Juvekar, Ashish; Lyssiotis, Costas A et al. (2016) Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell 164:433-46|