Targeting Metabolic Vulnerabilities Unique to Pancreatic Ductal Adenocarcinoma

Novel Approaches and New Therapeutics

Michael Karin (UCSD)

Reuben Shaw (Salk)

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 11%. Most patients die within 6 months of diagnosis from metastatic disease, but even patients who qualify for surgical resection eventually succumb to the disease. No targeted therapies are available. Unique to PDAC is a dense tumor stroma that restricts nutrient acquisition by the cancer cells, which bypass this obstacle through upregulation of alterative nutrient procurement and energy generating mechanisms. Key to upregulation of these mechanisms is the ratio of cleaved (cCol) and intact (iCol) collagen in the tumor stroma. Using preclinical models, we found that the cCol:iCol ratio dictates PDAC metabolism and growth by regulating the expression and activity of a specific collagen sensor called DDR1, thereby controlling the generation of mitochondria, the cellular power stations that provide PDAC cells with energy. The tumor cCol:iCol ratio, DDR1 activity and mitochondrial content strongly correlate with patient survival after resection. Importantly, high mitochondrial content predicts poor survival, suggesting that mitochondria reducing treatments may inhibit tumor growth. Indeed, we found that an FDA-approved antibiotic called tigecycline reduces mitochondrial content and curtails PDAC metabolism and growth in preclinical models. Here we propose to potentiate tigecycline’s anti-PDAC activity by complementing it with inhibitors of an enzyme, ULK1, needed for the recycling and repair of PDAC mitochondria. This novel approach, which will be tested in several preclinical models and fresh human PDAC slice cultures, should be highly effective in blunting PDAC growth by cutting off tumor energy supplies.