Therapeutic Induction of Tumor Selective Ferroptosis in Pancreatic Cancer

Dr. Olive was the recipient of a 2020 PanCAN Translational Research Grant for a project focused on a newly discovered way that cells can die, 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 have especially high levels of oxidation, which they counteract by using a lot of cysteine. This means that cancer cells are particularly dependent on cysteine to protect themselves from ferroptosis. The Olive lab's research has shown that depleting pancreatic tumors of cysteine can cause them to undergo ferroptosis while leaving normal cells unaffected, as the latter possess lower levels of oxidation. In particular, the team has 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 mice, 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's original project therefore proposed to combine cyst(e)inase with an immunotherapy approach and a drug that targets a protein called MEK. Through his one-year Translational Research Grant Extension funding, Dr. Olive and his team will further evaluate the combination treatment approaches using a leading-edge technique that allows the investigators to study individual cells and understand how genetic material (DNA) gets transcribed to RNA, which is a critical step toward creating proteins that impact cellular behaviors. There can be vast differences between cancer cells within a single tumor. Even malignant cells with identical DNA mutations can assume different states that vary in their biology, their genetic dependencies and their therapeutic vulnerabilities. Dr. Olive believes that the presence of cancer cells in different states within most pancreatic tumors underlies the ability of these tumors to resist treatment. By studying their different therapeutic sensitivities, the Olive lab is hoping to build combinatorial drug regimens that target the full range of variation within a patient's tumor. Dr. Olive and his colleagues have found that the impacts of MEK inhibition and cyst(e)inase treatment propagate through the tumor stroma, modulating the immunosuppressive tumor microenvironment. By studying how the cellular states of each distinct cell type within a tumor are impacted by treatment, they hope to develop a truly holistic understanding of therapeutic response and resistance, paving the way for refined regiments and future clinical testing in patients with pancreatic cancer.