MetaPanc – inhibition of glutamine metabolism as therapy against pancreatic ductal adenocarcinoma

Over the past 40 years, while there have been significant advances in 5-year survival rates for most cancers, the 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has barely improved and remains close to the levels seen in 5%. PDAC cell metabolism changes in response to the oxygen-deprived and nutrient-poor environment. One of the most significant metabolic changes occurs in the glutamine pathway. In normal cells, glutamine would enter the tricarboxylic acid (TCA) cycle. However, in PDAC cells, glutamine is diverted to another pathway to generate NADPH, maintain cellular redox balance, and ensure proliferation. The enzymes in this glutamine pathway, reprogrammed by oncogenic KRAS, are GLS, GOT2, GOT1, MDH1, and ME1. This pathway is not used extensively by non-tumor cells. A dual inhibitor of GOT1 and GOT2 would significantly block glutamine metabolism in PDAC cells, suppressing tumor growth without affecting the viability of non-tumor cells. This small-molecule-based inhibitor, indicated for the treatment of PDAC, would be administered orally and would increase patient survival by at least 251 times per year (TP3) compared to standard of care for PDAC treatment. The overall goal of the MetaPanc project is to demonstrate, in a preclinical setting, that dual small-molecule inhibition of GOT1 and GOT2 blocks PDAC growth. The specific objectives of MetaPanc are: (1) To design and synthesize dual inhibitors of GOT1 and GOT2; (2) To demonstrate that the dual inhibitors are capable of potently blocking the proliferation of PDAC model cells; (3) Demonstrate that dual inhibitors are able to block, with minimal side effects, PDAC growth in subcutaneous and orthotopic xenographs.

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ULL Team

• Miguel Xavier Fernandes
• José Manuel Padrón Carrillo