Therapeutic Induction of Tumor Selective Ferroptosis in Pancreatic Cancer

The ideal cancer therapy is a treatment that kills tumor cells without harming normal cells. Cells can be killed in a variety of ways, including through a recently discovered process called “ferroptosis.” This type of death occurs when a cell’s outer membrane is damaged by oxidation – a reaction with oxygen. Cells normally use a natural amino acid – a building block of proteins – called cysteine to prevent membrane oxidation. Dr. Olive and his research team have found that pancreatic tumor cells in particular have very high levels of oxidation, but they also use a lot of cysteine to counteract the oxidation. This means the cancer cells are particularly dependent on cysteine to protect themselves from ferroptosis. The investigators have shown in extensive preliminary data that depleting pancreatic tumors of cysteine can cause them to undergo ferroptosis, whereas normal cells are unaffected since they have lower levels of oxidation. In particular, Dr. Olive and colleagues evaluated a novel enzyme called cyst(e)inase, which breaks down cysteine in the blood, for its effects on pancreatic tumors using a genetically engineered mouse model of pancreatic cancer. Strikingly, cyst(e)inase induced ferroptosis specifically in pancreatic tumors and not in the normal tissues of the mouse, resulting in elevated levels of cell death in the tumors. By itself, cyst(e)inase did not completely cure the mice of their pancreatic tumors. Dr. Olive therefore proposes to combine cyst(e)inase with other agents that could sensitize the tumors to ferroptosis. Based on promising preliminary data, the team will test cyst(e)inase in combination with an immunotherapy drug and a targeted drug that blocks the activity of a protein called MEK. These studies will be carried out in a gold-standard genetically engineered preclinical model as well as in a novel model system developed by their team that utilizes thin living sections of human pancreatic tumors.