The birth and death of the cells in our bodies are tightly regulated processes essential for normal function of the body. Cell death is important for tissue regeneration, elimination of harmful cells and maintaining homeostasis. A reduction in cell death can cause tumor development and resistance to therapy. Cell death occurs by regulated (e.g., apoptosis) and non-regulated pathways (e.g., necrosis). Ferroptosis is a type of regulated cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis.
Ferroptosis is implicated in various forms of degenerative disease and damage resulting from reperfusion of ischemic tissue (e.g., following a stroke). Ferroptosis inhibitors have the potential to lead to new therapeutic options in the treatment of these conditions. In contrast, since cancer cells are particularly vulnerable to ferroptosis, they upregulate multiple systems to suppress or counteract it. The identification and characterization of these systems can identify targets that can be exploited to develop novel therapies to treat resistant forms of cancers.
In partnership with Professor Kivanc Birsoy’s lab at Rockefeller University and Professor Scott Dixon’s lab at Stanford University, Professor Derek Pratt from the Department of Chemistry and Biomolecular Sciences is investigating how some metabolites impact ferroptosis. For example, following the discovery of Prof. Birsoy’s team that tetrahydrobiopterin (BH4) synthesis is upregulated in cancer cells to protect them from ferroptosis, Prof. Pratt’s team demonstrated that BH4 can inhibit lipid peroxidation by behaving like a radical-trapping antioxidant similar to Vitamin E. Understanding the biochemical mechanisms that cause cancer is complex and needs a multidisciplinary approach.
Prof. Dixon’s lab at Stanford developed a microscopy-based cell assay to identify ferroptosis inhibitors and used their assay to screen key compound libraries for potential leads to therapeutics that can treat ferroptosis-related degenerative disease. One of the libraries was focused on repurposing FDA-approved drugs. Prof. Pratt’s team demonstrated that some of the hits inhibited lipid peroxidation (like BH4 and Vitamin E). On the basis of these and other discoveries, Profs. Pratt and Dixon are co-founders of Prothegen Inc., a start-up primarily focused on the development of ferroptosis inhibitors for the treatment of various forms of neurodegeneration.
