Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and new therapies are desperately needed. Our previous work has shown that PDAC have an altered metabolism and that oncogenic Kras plays a key role in this metabolic reprogramming. Importantly, we have identified a novel, glutamine (Gln) -dependent pathway that is necessary for PDAC growth through the generation of NADPH for the maintenance of redox balance (referred to as the Gln-redox pathway). This pathway is dependent on oncogenic Kras and is absolutely essential for PDAC growth both in vitro and in vivo, while being dispensable in normal cells. Thus, there may be an accessible therapeutic window. We have shown that oncogenic Kras controls flux through the Gln-redox pathway by regulating the relative expression of two key metabolic enzymes; GOT1 and GLUD1, thereby promoting the transamination of Gln-derived aspartate by GOT1 and repressing the canonical conversion of glutamate to alpha-ketoglutarate by GLUD1. Ultimately, NADPH and pyruvate are produced by malic enzyme (ME1). Additionally, our data demonstrate that the overwhelming majority of Gln- derived pyruvate produced by ME1 is not converted to lactate via lactate dehydrogenase. Specifically the isotopomer analyses suggest that this pool of pyruvate is directly tunneled into the mitochondria where it can be acted upon by pyruvate carboxylase (PC). Together, this supports the idea that a complex exists between ME1, the mitochondrial pyruvate transporter (MPC1/2), and possibly PC. Consistent with this concept, we have shown that suppression of either MPC1 or PC results in a significant accumulation of fully labeled aspartate in Gln tracing studies, suggesting that the Gln-redox pathway has been inhibited. Against this backdrop, we propose a series of in-depth, mechanistic studies to elucidate: i) the regulation of the pathway by oncogenic Kras; ii) the integration of this pathway with other ROS scavenging pathways in PDAC; iii) the metabolic fate of the pyruvate end product, and iv) the impact of the PDAC microenvironment in vivo on this unique Gln metabolism. Given the difficulties in developing inhibitors to Kras, targeting Kras-regulated metabolic pathways that are required for growth may provide novel entry points of attack in this devastating cancer. Thus, a complete understanding of this novel Gln-redox pathway will be critical to translate these findings to the clinic. SA1. T explore the regulation of glutamine metabolism and redox balance by oncogenic Kras. SA2. To investigate the fate of malic enzyme derived pyruvate in PDAC glutamine metabolism. SA3. To explore how the PDAC microenvironment impacts glutamine metabolism and redox balance in vivo under basal and stress conditions.
This proposal seeks to build on data from my laboratory showing that oncogenic Kras can reprogram glutamine metabolism in pancreatic cancer. Pancreatic cancer is highly lethal and current treatments such as chemotherapy and radiation are only minimally effective due to its profound therapeutic resistance. The results of these studies may have an important impact on the treatment of this disease.
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