There is currently no effective drug treatment for hemorrhagic stroke, a condition where a ruptured blood vessel causes bleeding in the brain. However, researcher Ke Jian Liu is exploring the repurposing of FDA-approved cancer drugs to treat this type of stroke. Liu’s research is backed by a five-year, $2.6 million grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, which extends through November 2029.
The American Stroke Association reports that hemorrhagic strokes make up about 13% of stroke cases. Intracerebral hemorrhage is one form where bleeding occurs within the brain. Stroke remains a major cause of disability and the fifth leading cause of death in the United States.
Liu’s work focuses on a novel mechanism involving zinc processes in the blood and brain, which are influenced by protein kinase inhibitors, a class of cancer drugs. Despite extensive studies, the mechanisms of brain damage from intracerebral hemorrhage are not fully understood. Damage is believed to be caused by red cell lysis and the toxic effects of released hemoglobin and its breakdown products, heme and free iron. Current therapeutic strategies targeting these blood components have been inadequate. Liu's lab has identified that endogenously formed zinc protoporphyrin (ZnPP), a compound in red blood cells made of porphyrin and zinc complexes, contributes to brain damage in such strokes.
“We think that this discovery opens new avenues for drug therapeutic intervention to treat hemorrhagic stroke,” said Liu, a professor in the Department of Pathology at the Renaissance School of Medicine at Stony Brook University and associate director of Basic Science at the Stony Brook University Cancer Center.
Liu and his team are targeting ZnPP formation in the brain. Initial findings with a selected compound inhibitor linked to ZnPP indicate that protein kinase inhibitors can reduce brain injury and enhance neurological outcomes in animal models of hemorrhagic stroke.
“Essentially, we conduct experiments in models of hemorrhagic stroke to investigate the mechanisms underlying ZnPP generation and neurotoxicity,” added Liu.
He noted that the FDA-approved cancer drugs do not inhibit ZnPP, and their hypothesis and findings emerged through staged research. Firstly, Liu’s lab found that ZnPP is generated during hemorrhagic stroke and is more neurotoxic than other known stroke injury compounds. Then, recognizing that ZnPP is produced via the enzyme ferrochelatase, they discovered that inhibiting ferrochelatase reduces ZnPP production and subsequent brain injury. They focused on kinase inhibitors with off-target effects on ferrochelatase unrelated to cancer treatments.
“We connected the dots and began testing some FDA-approved kinase inhibitors, which validated our speculation with ferrochelatase. So now we are exploring the potential of pharmacologically inhibiting ZnPP generation by investigating off-target ferrochelatase inhibition using these inhibitors,” explained Liu.
Currently, 82 small-molecule protein kinase inhibitors have received FDA approval for treating various cancers, such as leukemia, lymphoma, and breast cancer. This offers Liu and collaborators a wide range of kinase inhibitors to evaluate for their potential to inhibit ferrochelatase and compare results.
Liu anticipates that the research might redefine stroke researchers’ comprehension of intracerebral hemorrhage-induced brain damage and eventually lead to a new treatment for hemorrhagic stroke.
He and his collaborators are optimistic that if their treatment approach continues to demonstrate effectiveness and safety while improving outcomes in experimental models, human trial proposals could advance swiftly, as drug toxicity studies may not be necessary due to the pre-established FDA approval of the inhibitors.