Suffolk Reporter

There is currently no effective drug to treat hemorrhagic stroke, a condition caused by a ruptured blood vessel leading to bleeding in the brain. Stony Brook researcher Ke Jian Liu, PhD, aims to develop a treatment by repurposing FDA-approved cancer drugs. His research is backed by a five-year, $2.6 million grant from the National Institute of Neurological Disorders and Stroke, under the NIH, continuing through November 2029.

Hemorrhagic strokes make up about 13 percent of stroke cases, according to the American Stroke Association. Stroke remains a leading cause of disability and the fifth leading cause of death in the U.S. Liu's research delves into a mechanism involving zinc in the blood and brain, particularly affected by protein kinase inhibitors used in cancer treatment.

Current understanding of the brain damage from intracerebral hemorrhage is limited, with existing theories attributing it to red cell lysis and the toxicity of hemoglobin and its breakdown products. However, these have fallen short as therapeutic strategies. Liu's lab discovered that zinc protoporphyrin (ZnPP), a compound formed in red blood cells, contributes significantly to brain damage in hemorrhagic stroke.

"We think that this discovery opens new avenues for drug therapeutic intervention to treat hemorrhagic stroke," states Liu, Professor in the Department of Pathology at the Renaissance School of Medicine, Stony Brook University, and Associate Director of Basic Science at the Stony Brook University Cancer Center.

Liu's team targets ZnPP formation in the brain, finding that protein kinase inhibitors reduce brain injury and improve neurological outcomes in animal models. "Essentially, we conduct experiments in models of hemorrhagic stroke to investigate the mechanisms underlying ZnPP generation and neurotoxicity," says Liu.

Though FDA-approved cancer drugs don't inhibit ZnPP, Liu's research points to an enzyme, ferrochelatase, as generating ZnPP. They found that inhibiting this enzyme reduces ZnPP and subsequent brain injury. Testing focused on kinase inhibitors revealed their off-target effects on ferrochelatase unrelated to cancer treatment. "We connected the dots," Liu explains, testing FDA-approved kinase inhibitors to validate his findings.

With 82 FDA-approved kinase inhibitors available for cancer treatment, Liu and his team are actively comparing their impact on ferrochelatase inhibition. They believe their work could transform understanding of intracerebral hemorrhage-induced brain injury and lead to new hemorrhagic stroke treatments.

If experimental models further prove this treatment safe and effective, proposals for human trials could proceed briskly, benefitting from the existing FDA approval of these inhibitors, which negates the need for additional toxicity studies.