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Ke Jian Liu

METRO photo

By Daniel Dunaief

In the typical process of developing cures for medical problems or diseases, researchers explore the processes and causes and then spend years searching for remedies.

Ke Jian Liu. Photo by Jeanne Neville, Stony Brook Medicine

Sometimes, however, the time frame for finding a solution is cut much shorter, particularly when the Food and Drug Administration has already approved a drug treatment for another problem.

This could be the case for hemorrhagic stroke. Caused by a burst blood vessel that leads to bleeding in the brain, hemorrhagic stroke represents 13 percent of stroke cases, but accounts for 50 percent of stroke fatalities.

That’s because no current treatment exists to stop a process that can lead to cognitive dysfunction or death.

A researcher with a background in cancer and stroke, Ke Jian “Jim” Liu, Professor of Pathology and Associate Director or Basic Science at the Stony Brook Cancer Center who joined Stony Brook University in 2022, has found a mechanism that could make a hemorrhagic stroke so damaging.

When a blood vessel in the brain bursts, protoporphyrin, a compound that attaches to iron to form the oxygen carrying heme in the blood, partners up with zinc, a similar metal that’s in the brain and is released from neurons during a stroke. This combination, appropriately called zinc protoporphyrin, or ZnPP, doesn’t do much under normal conditions, but could be “highly toxic” in hypoxic, or low-oxygen conditions.

“We have done some preliminary studies using cellular and animal stroke models,” said Liu. “We have demonstrated on a small scale” that their hypothesis about the impact of ZnPP and the potential use of an inhibitor for the enzyme that creates it ‘is true.’”

These scientists recently received a $2.6 million grant over five years from National Institute of Neurological Disorders and Stroke, which is a branch of the National Institutes of Health.

Focusing on a key enzyme

After Liu and his colleagues hypothesized that the ZnPP was toxic in a low-oxygen environment, they honed in on ways to reduce its production. Specifically, they targeted ferrochelatase, the enzyme that typically brings iron and protoporphyrin together.

Iron isn’t as available in this compromised condition because it has a positive charge of three, instead of the usual plus two.

Liu discovered the role of zinc in research he published several years ago.

When a hemorrhagic stroke occurs, it creates a “perfect storm,” as the enzyme favors creating a toxic chemical instead of its usual oxygen carrying heme, Liu said. He is still exploring what makes ZnPP toxic.

The group, which includes former colleagues of Liu’s from the University of New Mexico, will continue to explore whether ZnPP and the enzyme ferrochelatase becomes an effective treatment target.

Liu was particularly pleased that currently approved treatments for cancer could be repurposed to protect brain cells during a hemorrhagic stroke. Indeed, with over 80 approved protein kinase inhibitors, which could work to stop the formation of ZnPP during a stroke, Liu and his colleagues have plenty of potential treatment options.

“We’re in a unique position that a clinically available drug that’s FDA approved for cancer treatment” could become a therapeutic solution for a potentially fatal stroke, Liu said.

To be sure, Liu and his colleagues plan to continue to conduct research to confirm that this process works as they suggest and that this possible therapy is also effective.

As with other scientific studies of medical conditions, promising results with animal models or in a lab require further studies and validation before a doctor can offer it to patients.

“This is an animal model, based on a few observations,” said Liu. “Everything needs to be done statistically.”

At this point, Liu is encouraged by these preliminary studies as the subjects that received an inhibitor are “running around,” he said. “You can see the difference with your own eyes. We’re excited to see that.”

Earlier hypotheses for what caused damage during hemorrhagic stroke focused on the release of iron. In research studies, however, using a chelator to bind to iron ions has produced some benefits, but they are small compared to the damage from the stroke. The chelator is “not really making any major difference,” said Liu.

The Stony Brook researcher did an experiment where he compared ZnPP with the damage from other metabolic products.

“ZnPP is several times more toxic than all the other things combined,” which is what makes them believe that ZnPP might be responsible for the damage, he said.

Proof of principle

For the purpose of the grant, Liu said the scientists were focusing on gathering more concrete evidence to support their theory. The researchers are also testing a few of the protein kinase inhibitors to demonstrate that they work.

In their preliminary studies, they chose several inhibitors based on whether the drug penetrates the blood brain barrier and that have a relatively high affinity for ferrochelatase.

“This opens the door for a new phase of the study,” Liu said. “Can we find the best drug that provides the best outcomes? We are not there yet.”

Removing zinc is not an option, as it is a part of 2 percent of the proteome, Liu said. Taking it out would “screw up the entire biological, physiological system,” he added.

Liu speculates that any future drug treatment would involve a relatively small dose at a specific time, although he recognized that any drug could have side effects.

In an uncertain funding climate in which the government is freezing some grants, Liu hopes that the financial support will continue through the duration of the grant.

“Our hope is that at the end of this grant, we can demonstrate” the mechanism of action for ZnPP and can find a reliable inhibitor, he said. “The next step would be to go to a clinical trial with an FDA-approved drug, and that would be fantastic.”

Ke Jian Liu

By Daniel Dunaief

Ke Jian “Jim” Liu, who arrived at Stony Brook University in late July, plans to help build effective, interdisciplinary research teams.

Ke Jian Liu

Most recently at the University of New Mexico, Liu joins Stony Brook as a Professor in the Renaissance School of Medicine’s Department of Pathology and Associate Director of Basic Science at the Stony Brook Cancer Center.

“In my mind, Stony Brook, research wise, is outstanding,” Liu said in an interview. “The quality of the faculty is excellent.”

Liu will rely on the team building experience he honed while serving as Distinguished Professor in the Department of Pharmaceutical Sciences and Associate Dean for Research in the College of Pharmacy at the University of New Mexico. He also worked for eight years at Dartmouth Medical School, where he focused on developing larger collaborations.

“I really enjoy working with people and building teams,” Liu said.

In a note announcing Liu’s arrival, Kenneth Shroyer, chair in the Department of Pathology, recognized Liu’s multidisciplinary approaches in his research. Shroyer explained that Liu has used techniques ranging from chemical to biochemical to biophysical, and from the molecular and cellular level to animal models, to answer specific biological questions.

Shroyer wrote that Liu would focus on opportunities for grant development within several programs. 

At the Cancer Center, Liu said he plans to continue the effort to help Stony Brook earn National Cancer Institute designation.

To achieve that designation, Stony Brook will need to continue to provide outstanding medical care, demonstrate community engagement and highlight what makes Stony Brook different from everyone else, he said.

“It takes a village to do that,” Liu said.

He praised the efforts of current Cancer Center Director Yusuf Hannun, who recently announced his plans to step down as head of the center, triggering a nationwide search for a replacement.

Liu said an ideal candidate for that position would have clinical experience.

Player coach

With a busy research effort and lofty leadership goals, Liu explained that he’s able to tackle numerous challenges at once.

“I consider myself a player coach,” he said. “I enjoy research. I have my own research grant and am working with my students and post docs.”

Liu typically maintains a lab with five to six people at different levels. His research has two branches, cancer and stroke, that most people likely consider unrelated, but for which he has found connections.

“People always think, ‘Cancer is cancer and stroke is stroke and they are two entirely different diseases,” Liu  said. As a basic researcher, however, he looks at the cells and the molecules involved in both conditions.

“At a molecular level, a molecule doesn’t care where it is,” he said. “When a disease develops, the biological fundamental process is the same. For me, it’s interesting to look at [whether] certain processes that occur in the brain also occur in cancer.”

Liu’s cancer research focuses specifically on the molecular processes that become carcinogenic when metals like arsenic enter people’s bodies. A well-described poison in numerous murder mysteries, arsenic can contaminate drinking water, get incorporated into crops like rice, or can appear in fruit juices.

When metal enters the body, it doesn’t just cause damage everywhere. It has to find a certain molecular target with which to interact.

What Liu and researchers in his lab have discovered is that the target for arsenic is often the same pathways the body uses in zinc. A transition metal, zinc provides an important element as a part of transcription factors that are critical in biological processes.

Arsenic, however, replaces zinc, which is “one of the major mechanisms for carcinogenesis,” Liu said.

Fortunately for residents of Long Island, arsenic isn’t as prevalent as it is in the midwest and the southwest.

“Long Island doesn’t have too much arsenic in drinking water,” Liu said, although people are still exposed to it through fruit juices, rice and other products.

Arsenic also causes vascular disease issues and anemia. People who develop these other conditions in response to arsenic are also at higher risk to develop cancer. The specific types of cancers arsenic causes are lung, skin and bladder cancer.

“Arsenic is the dirty bomb” in the body as it creates multiple problems, Liu said. “Arsenic interacts with those key zinc molecules.” 

Overlap between stroke and cancer

In highlighting the overlaps between the two fields of research, Liu related how the brain has one of the highest concentrations of zinc in the body.

When people have strokes, their brain cells have oxidative stress, which causes a flood of zinc into the brain tissue that also damages cells.

“We are trying to understand how zinc is released and how zinc causes damage to the brain,” Liu said.

Stroke and cancer also have molecular overlaps regarding oxygen. In a stroke, a blood clot causes a blockage of blood flow. Without oxygen, a situation called hypoxia, neurons start to die.

By contrast, a tumor grows in a hypoxic environment, using energy from sugars like glucose, rather than relying on oxygen for its growth.

Liu emphasized the importance of continuing to provide oxygen to brain regions around a clot even before trying to remove the clot or restore blood flow.

A goal for his 100th year

Originally from Beijing, China, Liu and his wife Jiao Ding enjoy traveling. Their daughter Sarah Liu is a resident at Vermont Medical Center and their son Evan Liu is a PhD student at Stanford.

An avid tennis player who plays the sport at least twice a week, Liu is looking forward to attending his first U.S. Open next year.

He and his former tennis partner in New Mexico joked that their goal is to be in the top 20 in the United States when they are 100 years old.

Liu chose the American name “Jim” because it sounds similar to the second syllable of his given name, Ke Jian.

“If people can’t pronounce your name, they shy away,” he said. He believes it’s important to “make yourself adaptable.”