Approved Cancer Drugs May Have Potential to Treat Hemorrhagic Stroke

There is currently no effective drug to treat a hemorrhagic stroke, when a ruptured blood vessel causes bleeding into the brain. Researcher Ke Jian Liu, PhD, however, believes that a drug treatment for hemorrhagic stroke may emerge by way of repurposing certain drugs that are already U.S. Food and Drug Administration (FDA) approved to treat cancer. His approach and experiments are supported by a five-year $2.6 million grant from the National Institute of Neurological Disorders and Stroke, a branch of the National Institutes of Health (NIH). The grant runs through November 2029.

According to the American Stroke Association, hemorrhagic strokes account for 10 -15% (13%) of all stroke cases, with higher rates in low and middle-income countries and among men.  One form of this type of stroke causes blood bleeds within the brain (intracerebral hemorrhage). Overall, stroke is a leading cause of disability to Americans and the fifth leading cause of death.[1]

According to a study published in JAMA, hemorrhagic stroke mortality rose significantly in the US between 1990 and 2019, and the overall stroke mortality decline slowed in recent years, with variations by age and region. [2]

Liu’s research is based on his discovery of a novel mechanism related to processes of zinc in the blood and brain, which is affected by a class of cancer drugs called protein kinase inhibitors.

Not well understood
Despite extensive research, the mechanisms of intracerebral hemorrhage-induced brain damage are not well understood. This damage is thought to be mediated through red cell lysis and toxicity of released hemoglobin and its degradation products, heme and free iron. But therapeutic strategies on hemoglobin, heme, iron and other blood components in edema formation have fallen short. Liu’s lab uncovered that endogenously formed zinc protoporphyrin (ZnPP), a complex in red blood cells made up of the compound porphyrin and complexes of zinc, contributes to intracerebral hemorrhage-induced brain damage.

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

Zinc protoporphyrin in the brain
He and colleagues are targeting the formation of ZnPP in the brain. Their initial findings with a selected compound inhibitor that connects to ZnPP demonstrated that protein kinase inhibitors can reduce brain injury and improve 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,” says Liu.

He points out that the FDA-approved cancer drugs do not inhibit ZnPP, and that he and his team reached their hypothesis and conclusion through research taking several steps.

First, his lab discovered that ZnPP is generated during hemorrhagic stroke and that ZnPP is more neurotoxic than any other known compounds involved in stroke brain injury. Second, since ZnPP is known to be generated via an enzyme called ferrochelatase, Liu and colleagues tested and found that inhibiting ferrochelatase does decrease ZnPP generation and reduce brain injury following stroke. And third, they searched for clinically applicable ferrochelatase inhibitors. They centered on kinase inhibitors, which possess off-target effects on ferrochelatase not related 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,” explains Liu.

Small-molecule protein kinase inhibitors
Protein kinases play essential roles in the pathogenesis of many illnesses, hence small-molecule protein kinase inhibitors have become one of the most important drug targets in the past 20 years. [3]

To date, the FDA has approved 82 small-molecule protein kinase inhibitors for treating a variety of cancers, including leukemia, lymphoma, and breast cancer. In addition, some protein kinase inhibitors are used in the treatment of non-malignancies, including rheumatoid arthritis, chronic immune thrombocytopenia, myelofibrosis and polycythemia vera, idiopathic pulmonary fibrosis, renal graft vs. host disease, glaucoma, rheumatoid arthritis, Crohn disease, and ulcerative colitis. [3][4]

The availability of a large number of approved kinase inhibitors provides many options for Liu and colleagues to test multiple agents in relation to inhibiting ferrochelatase and to compare the results.

Liu thinks that the research could potentially transform stroke researchers’ understanding of intracerebral hemorrhage-induced brain injury and ultimately provide a new treatment for hemorrhagic stroke.

He and fellow investigators believe that if the treatment approach continues to prove to be effective, safe, and improve outcomes after hemorrhagic stroke in their experimental models, proposals for human trials could progress quickly, given that drug toxicity studies would not be required because of the FDA-approved status that already exists with the inhibitors.

Reference
[1] Hemorrhagic Stroke. What is Hemorrhagic Stroke? American Stroke Association. Online. last accesses on March 31, 2025.
[2] Renedo D, Acosta JN, Leasure AC, Sharma R, Krumholz HM, de Havenon A, Alahdab F, Aravkin AY, Aryan Z, Bärnighausen TW, Basu S, Burkart K, Coberly K, Criqui MH, Dai X, Desai R, Dharmaratne SD, Doshi R, Elgendy IY, Feigin VL, Filip I, Gad MM, Ghozy S, Hafezi-Nejad N, Kalani R, Karaye IM, Kisa A, Krishnamoorthy V, Lo W, Mestrovic T, Miller TR, Misganaw A, Mokdad AH, Murray CJL, Natto ZS, Radfar A, Ram P, Roth GA, Seylani A, Shah NS, Sharma P, Sheikh A, Singh JA, Song S, Sotoudeh H, Vervoort D, Wang C, Xiao H, Xu S, Zand R, Falcone GJ, Sheth KN. Burden of Ischemic and Hemorrhagic Stroke Across the US From 1990 to 2019. JAMA Neurol. 2024 Mar 4;81(4):394–404. doi: 10.1001/jamaneurol.2024.0190. Epub ahead of print. PMID: 38436973; PMCID: PMC10913004.
[3]vRoskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016 Jan;103:26-48. doi: 10.1016/j.phrs.2015.10.021. Epub 2015 Oct 31. PMID: 26529477.
[4]Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2024 update. Pharmacol Res. 2024 Feb;200:107059. doi: 10.1016/j.phrs.2024.107059. Epub 2024 Jan 11. PMID: 38216005

Featured image:© 2024  – 2025 Zyanya Citlalli Licensed under the Unsplash+ License

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