Disabling Metastasis by Targeting the Ferroptosis Protection Mechanism of Serum
Abstract
Most women diagnosed with epithelial ovarian cancer (OVCA) first go through surgical removal and chemotherapy and enter a period of remission. However, this initially promising response is often followed by recurrence with metastasis to the peritoneal cavity (belly) or other distant organs. Such unfortunate events often occur within months, but sometimes even years later. Metastatic tumors are often unresponsive to the same chemotherapy initially effective for the original tumor, leading to unfortunate suffering and death. Therefore, we urgently need to identify new treatment approaches to reduce metastasis. During metastasis, tumor cells need to dissociate from their neighboring cells, migrate and travel long distances to metastasize. While the traditional view is that these metastatic cells travel via ascites and in the belly, several recent studies have shown that many metastasis OVCA actually occur through the bloodstream to settle in the final destination organs. However, very little is known about how we can eliminate these traveling cells to reduce metastasis. We and others have found that these detached and traveling cancer cells, even when they have become resistant to chemotherapy, are very sensitive to a special kind of cell death called ferroptosis. An obvious question is: if these traveling tumor cells are so sensitive to ferroptosis, how can they survive ferroptosis and make it all the way to their destinations and establish metastasis? We think we have found the secrets. Our research has found that blood and serum protect traveling cancer cells from ferroptosis and explain why these cells don’t die during their travel and can form metastasis. However, our research has found that two FDA-approved drugs, auranofin (for joint pain) or bezafibrate (for high lipids), can abolish this protection by blood or serum, making them sensitive to ferroptosis again. Therefore, we will test whether we can push these traveling tumor cells toward ferroptosis to reduce metastasis as new treatments. Our objective is to identify novel treatment strategies to prevent or eliminate metastatic ovarian cancer, which is highly relevant to the vision and mission of OCRP to eliminate ovarian cancer and develop and validate models to understand the metastasis, treatment response, and recurrence of ovarian cancer. What Types of Patients Will It Help and How Will It Help Them? Most women diagnosed with ovarian cancer are at risk for metastasis. Therefore, our efforts to reduce or potentially eliminate metastatic OVCA will benefit the majority of women with advanced epithelial ovarian cancer for whom there are currently no such types of treatment. What Are the Potential Clinical Applications, Benefits, and Risks? We will find out whether triggering ferroptosis, a new form of cell death, can be used to eliminate metastatic OVCA, especially when the protective effects of blood are disabled by two FDA-approved drugs, auranofin or bezafibrate used by billions of people. If successful, this will lead to an entirely new regimen of treatment that targets metastatic tumor cells’ survival. Several ferroptosis-inducing agents are in early clinical development. Therefore, depending on the progress of drug development and regulatory procedures, they could be available in 5-10 years. Risks include the possibility of undesirable side effects, as is true with any drug. Potential benefits are the ability to reduce metastatic and treatment-resistant OVCA. What Is the Potential Impact on the Health and Welfare of Military Service Members and Their Families? Military Service Members, of which nearly 15% are women, as well as the women in their Families, are all vulnerable to ovarian cancer, with potentially increased risk from exposure to ionizing radiation and toxic chemicals during their service. The novel therapies will potentially benefit the health and welfare of these Service Members and their families by reducing
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310498
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army