Tags Posts tagged with "Dr. Yusuf A. Hannun"

Dr. Yusuf A. Hannun

Maurizio Del Poeta in his laboratory at Stony Brook University. Photo by Antonella Rella

By Daniel Dunaief

Researchers at Stony Brook University, the University of Arizona and Wake Forest University School of Medicine in North Carolina may have found an enzyme that drives the worst COVID-19 symptoms. Secreted phospholipase A2 group IIA, or sPLA2-IIA may lead to severe symptoms and death, making this enzyme a potential therapeutic target.

P116, Maurizio DelPoeta, Microbiology

In an examination of plasma samples from 127 patients hospitalized at Stony Brook University Medical Center between January and July 2020 and a mix of 154 patient samples from Stony Brook and Banner University Medical Center in Tucson between January and November 2020, scientists including Distinguished Professor Maurizio Del Poeta of the Renaissance School of Medicine at Stony Brook University found that 63 percent of people with concentrations of the enzyme that were over 10 nanograms/ milliliter generally died. Most healthy people have circulating levels of the enzyme around 0.5 nanograms/ milliliter.

“It is possible that sPLA2 levels represent a tipping point and when it reaches a certain level, it is a point of no return,” said Del Poeta.

The collaborators involved in the study, which was published this week in the Journal of Clinical Investigation, were encouraged by the finding.

“This is exciting as it is leading to really novel connections for COVID-19,” Yusuf Hannun, Director of the Cancer Center at Stony Brook and a contributor to the research who participated in the discussion and data analysis, explained in an email. “It may lead to both diagnostics (for risk prediction) and therapeutics.”

Looking closely at the levels of sPLA2-IIA together with blood urea nitrogen, or BUN, which is a measure of the performance of the kidney, the researchers in this study found that the combination of the two measures predicted mortality with 78 percent accuracy.

“That is an opportunity to stratify patients to those where an inhibitor” to sPLA2-IIA could help patients, said Floyd Chilton, director of the University of Arizona Precision Nutrition and Wellness Initiative and senior author on the paper, said.

While they found a difference in the amount of the enzyme between healthier and sicker patients, the scientists recognize that this could reflect a correlation rather than a causation. The progression of the disease and the threat to people’s lives may come from other contributing factors that also intensify the severity of the illness.

“These studies do not establish causality at the moment, but the strength of the correlation and the known functions of this enzyme raise the possibility of participating in the pathology of the disease,” Del Poeta explained.

Floyd Chilton. Photo from University of Arizona

Indeed, Chilton has studied sPLA2-IIA for over three decades and has described some patterns in other diseases, including sepsis.

The enzyme performs an important role in fighting off bacterial infection by destroying microbial cell membranes. When the concentration of sPLA2-IIA rises high enough, however, it can threaten the health of the patient, as it can attack and destroy cells in organs including the kidney.

The enzyme “plays a critical role in host defense,” said Chilton. “These same systems can really turn on the host.”

In order to determine a causative link between sPLA2-IIA and the progression of the disease, Chilton, Del Poeta and others will need to increase their sample size.

“We’ve been very fortunate at getting individuals at some of the top global organizations… who have connected me with medical centers” that have a larger patient population, Chilton said. These executives may be able to expedite the process of expanding this study.

In the 1990’s, scientists studied an inhibitor that had the ability to act on the enzyme. 

That effort had mixed results in phase 2 clinical trials.

“In 2005, the first phase of the phase 2 clinical trials were highly encouraging,” Chilton said. “It really inhibited mortality at 18 hours” by reducing severe sepsis. The second part of those tests, which used a slightly different protocol, failed.

While he’s not a clinical trials expert, Chilton is hopeful that researchers might find success with this same drug to treat COVID-19.

Only clinical trials would reveal whether inhibitors would work with COVID-19, scientists said.

As with many drugs, inhibitors of sPLA2-IIA have side effects.

By blocking the activity of these enzymes, “we do also decrease the production of arachidonic acid, which is a precursor of prostaglandins,” said Del Poeta. “In condition of hyperinflammation, this is a good thing, but prostaglandins are also important in a variety of cellular functions” including blood clots and starting labor.

Chilton pointed out that sPLA2-IIA is similar to the active enzyme in rattlesnake venom. It can bind to receptors at neuromuscular junctions and disable the function of these muscles, he explained.

In nature, some animals have co-evolved with snakes and are no longer susceptible to these toxins. Researchers don’t yet understand those processes.

While copying such evolutionary solutions is intriguing, Chilton said he and his collaborators are “much more interested in the inhibitors” that were taken through clinical trials in 2005 because that might present a quicker solution.

The research collaboration started with Chilton, who partnered with Arizona Assistant Research Professor Justin Snider. The first author on the paper, Snider earned his PhD at Stony Brook, where he knew Del Poeta well.

Snider “knew what a great researcher [Del Poeta] was. I also knew [Hannun] in a former life. We were both working on similar biochemistry 20 to 25 years ago,” Chilton said.

Chilton called the efforts of his Stony Brook collaborators, including Research Assistant Karen You, Research Associate Professor Chiara Luberto and Associate Professor Richard Kew,  “heroic” and explained that he and his colleagues recognize the urgency of this work.

“I’ve been continuously funded by the [National Institute of Health] for 35 years, and I’m very grateful for that,” Chilton said. “There is nothing in my life that has felt this important,” which is why he often works 18 hour days, including on weekends.

After studying the effects of variants on the population, Chilton recognized that building a firewall against COVID-19 through vaccinations may not be enough, especially with the combination of lack of access to the vaccine for some and an unwillingness to take the vaccine from others.

“We may have to go to the other side of the equation,” HE said. “We’ve got to move to specific therapeutics that are agnostic to the variant.”

Joel Saltz. Photo from SBU

By Daniel Dunaief

In the battle against cancer, doctors and scientists use targeted drugs to treat the disease. They also employ radiation, starve it of the nutrients it might need to grow, block key metabolic pathways in its development and encourage the immune system to attack these genetically misdirected cells that grow out of control. A developing field in this battle includes the use of computers, artificial intelligence and math.

Joel Saltz, the Cherith Chair of Biomedical Informatics at Stony Brook University, recently teamed up with researchers from Emory University and the University of Arkansas and won an $8 million grant from the National Cancer Institute to coordinate radiology and pathology information in the battle against cancer.

“By gathering more information, researchers can understand better what’s happening, what might happen and how best to treat cancer,” Saltz said. The grant will be divided equally among the three institutions over the course of five years. Saltz will be collaborating with Ashish Sharma at Emory and Fred Prior at the University of Arkansas.

Saltz has been working with Sharma for several years, when the two were at Ohio State and then moved together to Emory. This is Saltz’s first major grant with Prior, although the two have also known each other for years and have been working in the same NCI program.

Prior has considerable expertise in radiology, while Saltz is adding his pathology background to the mix. Radiology has used digital imaging for a long time and, until recently, pathology data was collected on glass slides. Saltz is helping bring digital pathology to this effort.

“We had been on panels for many years with NCI saying we need to do this sort of” collaboration, Saltz added, and now the trio is putting that idea to work.

Yusuf Hannun, the director of the Cancer Center at Stony Brook, sees the potential for this type of collaboration. “This is a very important effort that builds on several areas of outstanding strength” at the Cancer Center, the director explained in an email.

Exploring information from digitized radiology and pathology samples will “allow us to understand individual cancers at a much higher level. It should improve accuracy in diagnosis [and offer an] ability to provide better informed prognosis” and individual therapy, Hannun continued.

Researchers on the current grant, which is part of the Information Technology for Cancer Research, plan to expand resources for integrative imaging studies, build on the capacity to acquire high-quality data collections, dedicate resources to support reproducible research and increase community engagement.

Saltz will use the portion of the Stony Brook funds to develop new software integration tools and curation and work with researchers to analyze and understand their patient data. Over time, he will also hire additional staff to build out this expertise. He has collaborated with Kenneth Shroyer, chair of the Department of Pathology at Stony Brook, on pancreatic and ovarian cancer and on breast cancer with pathology professor Patricia Thompson, who is also director of basic science at the Cancer Center. Shroyer “plays an important role” in all his research, Saltz said.

“Digital pathology will supplement that art of surgical pathology with quantitative data, to improve diagnostic accuracy,” Shroyer wrote in an email, which will “inform decisions on how to optimize therapeutic intervention for the treatment of cancer and many other diseases.”

Shroyer interviewed Saltz before Stony Brook hired its first bioinformatics chair. “Based on his research focus, including his pioneering efforts in digital pathology, he clearly stood out as my top choice.”

Saltz and Shroyer have generated maps of patterns for immune cells in tumors. “We and others have shown that these are related to how patients respond to treatment,” Saltz said. He described his work with these scientists as “basic clinical cancer research,” in which he develops and enhances technology to understand various types of cancer.

This particular grant is “more about technology and curation,” Saltz said. “People are developing new algorithms, in artificial intelligence and machine learning.” By making this information available, scientists from around the world who have insights into the specific types of cancer can use it to predict responses to treatment and develop and refine the algorithms that underlie the computer analysis.

Using specific cancers from radiology and pathology studies is akin to sitting in a football stadium and examining a blade of grass from the bleachers, Saltz suggested, borrowing from a phrase he’d heard at a recent panel discussion with Liron Pantanowitz from the Department of Pathology at the University of Pittsburgh Medical Center.

“What we do is we create catalogs of every blade of grass and every worm and weed,” Saltz added. “It’s a huge database problem” in which he is integrating software development.

Hannun, who has been working to help Stony Brook University earn a National Cancer Institute designation, suggested that this bioinformatics work is “a critical component of our plans” and represents an area of exceptional strength.”

Cancer bioinformatics is “one of the main pillars of our research program and it integrates well with our efforts in imaging, metabolomics, improved diagnostics and improved therapeutics,” Hannun explained.

As for his department, Saltz said Stony Brook will have its first biomedical informatics Ph.D. graduate at the end of 2017. Yanhui Liang joined Stony Brook when Assistant Professor Fusheng Wang came to Long Island from Emory. Xin Chen will graduate in May of 2018.

The doctoral program, which launched last year, has five current students and “we’re hoping to get a bigger class this year,” Saltz said. “Informatics involves making techniques for better health care,” Saltz said. People with medical degrees can do fellowship training in clinical informatics.

A resident of Manhasset, Saltz lives with his wife Mary, who is an assistant clinical professor of radiology at Stony Brook University. Over the course of the next five years, Saltz said he believes this grant will continue to allow him and his collaborators to develop tools that will help provide insights into cancer research and, down the road, into personalized cancer treatment.

CHECK PRESENTATION: From left, Dr. Lina Obeid, Leg. Kara Hahn, Dr. Yusuf A. Hannun, Gloria Rocchio, Dr. Scott Powers, Carol Simco and Dr. Jun Lin. Photo from WMHO

On March 27, Stony Brook University’s Cancer Center received a donation of $40,000 from the Ward Melville Heritage Organization (WMHO), which were funds raised from WMHO’s 23rd Annual Walk for Beauty and Hercules Run held on Oct. 23 of last year in historic Stony Brook Village.

Suffolk County Legislator Kara Hahn (D-Setauket) and co-chair, Walk for Beauty; Gloria Rocchio, president, Ward Melville Heritage Organization and co-chair, Walk for Beauty; and Carol Simco, co-chair, Walk for Beauty, officially presented the check to Dr. Yusuf A. Hannun, director, Stony Brook Cancer Center, and vice dean, Cancer Medicine. Joining them were Dr. Jun Lin and Dr. Scott Powers, cancer researchers whose projects received funds raised from the 2015 Walk for Beauty, and Dr. Lina Obeid, dean for research, Stony Brook University School of Medicine.

Also present, but not shown, were Councilwoman Valerie M. Cartright (D-Port Jefferson Station), WMHO Trustee Anna Kerekes and Walk for Beauty committee members. Since its inception in 1994, Walk for Beauty has raised over $1.365 million toward breast cancer research. Funds raised also help to supply items such as wigs and prostheses for SBU Cancer Center patients. The event is an all-volunteer initiative with no administrative costs.

Registration is now open for the 2017 Walk for Beauty, which will take place on Sunday, Oct. 22. Visit www.wmho.org/wfb for more information.