We urgently need to identify new treatment approaches that can effectively reduce the burden of recurrent metastatic OVCA. We know that OVCA cells that are detached from the tumor and in the process of metastasizing are somehow protected against the normal bodily safeguards that otherwise destroy such cells. We have recently found that this protection comes from components present in the abdominal fluid (ascites) that often accumulates abnormally in ovarian cancer patients. Here, we propose to determine more specifically how these detached OVCA cells survive during metastatic progression and to test the ability to deactivate the protective mechanisms present in the ascites fluid as an exciting new approach to prolonging survival for OVCA patients. During metastasis, tumor cells need to dissociate from their neighboring cells and the original tumor(s) and travel long distances, often through the ascites or blood stream, to reach a suitable place to attach in the abdominal cavity. These cells can also metastasize through the blood stream. We and others have published that these detached and traveling cells have a specific need for cystine, a non-essential amino acid, for their survival. Compared to normal cells, these traveling ovarian cancer cells often have increased demands for cysteine from the surrounding environment. The removal of cystine rapidly triggers a special kind of cell death called “ferroptosis”, but in cell culture, ascites fluid collected from OVCA patients can protect these traveling cancer cells from ferroptosis. This may help explain why these cells don’t die during their travels and are able to settle down in the abdomen and metastasize. Here, we will determine how ascites fluid protects traveling OVCA cells from ferroptosis, attempt to block this protection, and determine if drugs that we know are able to activate ferroptosis can be used on these traveling cells to reduce metastasis. If successful, this will lead to an entirely new treatment regimen that targets the mechanism(s) that enables these metastatic tumor cells to survive during their migration. This proposal is based on our dramatic preclinical observations and includes available drugs that can effectively induce ferroptosis. Several ferroptosis-inducing agents are already being developed by drug companies. Depending on drug development progress and regulatory procedures, these drugs could be available in 5-10 years. Potential benefits are a newly identified ability to kill metastatic OVCA resistant to current chemotherapy with the potential to prolong survival. Positive results will prompt future pilot clinical trials in patients.
Dr. Chi is a physician-scientist and a co-director of the Cancer Biology Research Program at Duke Cancer Institute. He has a long-term research interest in the stress adaption and metabolism of cancer cells. Recently, he has been working on the determinants of ferroptosis, a newly recognized form of cell death that is characterized by iron dependency and lipid peroxidation. Previously, his lab identified the profound cystine addiction of renal cell carcinoma, breast cancer cells, and ovarian cancer cells. Based on the concept that cystine deprivation triggers ferroptosis due to the unopposed oxidative stresses, has lab has performed functional genomic screens to identify many novel genetic determinants of ferroptosis, including DNA damage response, cell density, and metastasis. The current award will allow Dr. Chi and his lab members to understand novel environmental determinants of ferroptosis for ovarian cancers and their roles in the metastatic ovarian cancer.