The scientific work that will be performed in this project is to explore new pathways of cancer treatment with particular focus on pancreatic cancer. These new ways of treatment are based on changing the functions of different signaling and metabolic pathways such as NADPH oxidase (NOX), reactive oxygen species (ROS) and metabolism which are known to be up-regulated or malfunctioning in cancer cells. By using different chemicals such as NOX inhibitors, digitoxin and ketone bodies inhibit their activity and thereby decrease the cell viability of the cancer cells. Focusing treatment on the differences between normal / cancer cells would help develop methods that inhibit cancer cells with less negative effects on normal cells.
Pancreatic Ductal Adenocarcinoma
Pancreatic Ductal Adeno Carcinoma (PDAC) is a tumour in the exocrine part of the pancreas, in the acinar cells that excrete digestive enzymes into the intestine. PDAC has the poorest prognosis of all cancers, with a five-year survival rate less than 5%. Most PDACs are highly resistant to chemo-and radiotherapy. Despite extensive treatment the median survival is only 20-23 months. Risk factors for PDAC are smoking, obesity, T2DM, chronic pancreatitis and heredity to PDAC.
Type 2 Diabetes Mellitus
T2DM is predicted to be one of the greatest health hazards in the future (World Health Organization, 2016). Having T2DM gives an increased risk for all kinds of cancer but particularly cancer of the pancreas.
Cancer has historically been considered as a genetic disease. Much effort have been dedicated to search for the “one” mutation causing normal cells to become cancer cells. But there is one property of cancer cells that is common for all cancers and that is the shift from oxidative phosphorylation in the mitochondria to aerobic glycolysis in the cytosol. The phenomena is called the Warburg effect, and it makes it possible for cells to aerobically, in a high rate, metabolize glucose to lactate. As a side effect the levels of reactive oxygen species (ROS) in the cell increases, which alters the normal homeostatic levels. In cancer cells elevated levels of ROS can also be caused by reduced activity of antioxidants, imbalanced levels of intracellular calcium, increased activity of certain receptors, higher levels of growth factors and increased intracellular production of ROS by NADPH oxidases (NOX).
PhD-project, Heléne Lindholm: NOX, ROS and metabolism in Pancreatic Ductal Adenocarcinoma