Targeting Environmental Ferroptosis Protection as a Novel Therapeutic Strategy for Metastatic Renal Cell Carcinoma
Abstract
Scientific Objective and Rationale for the Proposed Project: Despite all the new development in diagnosis and treatment for kidney cancer, the prognosis and outcomes are still unacceptable for patients with advanced and metastatic kidney cancer. One special characteristic of kidney cancer is its association with blood. Many kidney cancers will grow into blood, a process called vascular invasion. In addition, most of the metastasis of kidney cancer occurs through the bloodstream instead of the lymphatic system. This preferential association with blood has been a mystery and solving such a mystery may unlock new insights to reduce the metastasis of kidney cancers. The proposed study is based on an exciting insight we have gained into a potential explanation. We and other scientists have found that most kidney cancer cells are very vulnerable to ferroptosis, a special kind of iron-dependent cell death we are just learning about. In addition, many changes during metastasis would make them even more sensitive to ferroptosis. One study on melanoma cells has confirmed our prediction that traveling tumor cells in the bloodstream undergo ferroptosis. If this is the case, how can traveling kidney cancer cells survive ferroptosis and establish metastasis? We may have solved the mystery. We have found that while the metastatic RCC are highly sensitive to ferroptosis, they can be protected from ferroptosis by the blood and serum. Therefore, the traveling RCC tumor cells in the bloodstream are continuously protected and chaperoned by the blood during their journey to metastasis which can allow survival and establish metastasis. FY22 KCRP Focus Area(s) to be addressed: (1) Conduct basic biology research better to understand etiology and cancer progression, metastatic disease. (2) Develop novel therapeutic strategies for the treatment of kidney cancer. Describe the ultimate applicability of the research: There are multiple ways the proposed research can be applied to help patients. First, it is possible that bezafibrate and other lipid-lower drugs can be safely used to prevent metastasis by disabling the ferroptosis protection by blood. In addition, these methods can be used to treat metastatic kidney cancers by combining with the drugs that kill RCC by ferroptosis, especially when the RCC has become unresponsive to other treatments. Finally, ferroptosis has been shown to enhance immunotherapy and may provide combination therapeutics to immunotherapy for patients with kidney cancer. What types of patients will it help, and how will it help them? Most patients diagnosed with kidney cancer are at risk for metastasis and clear-cell types are particularly sensitive to ferroptosis. Therefore, our efforts to reduce or potentially reduce or eliminate metastatic kidney cancer will benefit most patients at risk for metastasis and for whom there are currently no effective treatments. What are the potential clinical applications, benefits, and risks? We will find out whether interfering with blood protection can be used to eliminate metastatic RCC by triggering ferroptosis. If successful, this will lead to an entirely new regimen of treatment that targets metastatic tumor cells survival in the blood. A potential benefit is the ability to reduce metastatic RCC. Risks include undesirable side effects, as is true with any drug. What is the projected time it may take to achieve a clinically relevant outcome? Our research has pointed to a potential for FDA-approved bezafibrate used by billions of people. 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 to 10 years. What are the likely contributions of this study to advancing the field of cancer research and/or patient care? Find out the novel role of serum and blood as determinants of metastasis by ferroptosis protection. S
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310850
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army