Increased intra-tumoral glucose level is associated with enhanced chemotherapeutic response in pancreatic cancer

Pancreatic tumors are refractory to current chemotherapies, and there are no effective alternative therapies available for patients with pancreatic cancer (PC). We present an innovative approach to improve chemotherapy efficacy in preclinical models of pancreatic cancer. The effectiveness of various chemotherapies, including standard of care FOLFIRINOX, was remarkably enhanced by inducing a state of hyperglycemia. This was achieved by either providing animals with a high glucose diet or by a pharmacologic method involving streptozotocin coupled with long-acting insulin. Comprehensive integrative analyses revealed a key metabolic pathway, glutathione biosynthesis, mitigated by the high glucose diet. Combining chemotherapies with either the high glucose diet or an inhibitor of glutathione biosynthesis as a feasible approach caused a significant survival benefit in mice bearing orthotopic pancreatic tumors. Overall design: Orthotopic tumors under hyperglycemic (D30) compared to normoglycemic condition. Five independent biological replicates were used.