Research roundup: Breakthroughs from CWRU labs

Research updates

Breakthroughs from the labs of CWRU School of Medicine

Understanding and treating deadly esophageal cancers

Cancer of the esophagus, especially esophageal adenocarcinoma (EAC), is highly lethal, with 80% of patients dying within five years of diagnosis, according to Kishore Guda, DVM, PhD, an associate professor at the School of Medicine. Patients with Barrett’s esophagus, a condition marked by a change in normal cells lining the esophagus, are at high risk of developing EAC.

With a five-year, $11.2 million grant from the National Cancer Institute, Guda and collaborators at CWRU and University Hospitals (UH) hope to learn what causes—and how to reduce and treat—such Cancers.

Guda and Amitabh Chak, Ph.D., the Younker-Ponsky Professor of Diagnostic Intervention and a physician at UH—both of whom are members of the Case Comprehensive Cancer Center—are leading this project, adding to the two decades of work they’ve put into this form of cancer.

With this new round of funding, they will focus on how these types of cancers originate—specifically, the molecular and genetic factors that trigger why and how Barrett’s esophagus develops and progresses to esophageal cancer.

This latest grant builds upon multiple areas of Guda and Chak’s previous research—including their recent identification of an inherited mutation in a gene, Caveolin-3, linked to EAC.

“With this discovery, we will be able to identify early those at a high risk of developing EAC in their lifetime,” Guda said of the research, which was published in Gastroenterology, “and accordingly tailor screening, lifestyle and treatment strategies to prevent cancer development.”

Predicting the power of chemotherapy in the first round

Nearly 80% of breast cancer patients show partial or no response to conventional chemotherapy, but it takes four to six months and multiple cycles of treatment to even find out.

With a five-year, $3.05 million grant from the National Institutes of Health and National Cancer Institute, researchers at Case Comprehensive Cancer Center and UH are studying whether a new magnetic resonance imaging exam can predict chemotherapy’s effectiveness for a woman with breast cancer based on a single round of treatment. Their goal: save women from unnecessary treatments while helping physicians seek alternative, more effective options without wasting precious time.

“This study has great potential to bring real survival and quality-of-life benefits to our breast cancer patients,” said Yong Chen, PhD, an assistant professor of radiology.



Chen is leading the study with Holly Marshall, MD, an associate professor of radiology at the School of Medicine and division chief of breast imaging at UH, and Dan Ma, Ph.D. (GRS ’15, biomedical engineering), an assistant professor of biomedical engineering. They’re using magnetic resonance fingerprinting (MRF), which essentially examines multiple tissues in the body with a single, time-efficient image, or “fingerprint.” Preliminary results of the researchers’ work suggest MRF methods can accurately assess therapeutic response seven to 10 days after the initial chemotherapeutic cycle—creating the opportunity for significantly improved patient care and flexibility aimed at a more personalized therapy for many women.

A new approach to stop cancer growth?

Overexpression of the protein LSD1 (lysine-specific histone demethylase 1A) has been identified as a driver of cancer and heart disease, with some researchers looking to slow cancer growth by stopping LSDI’s catalytic activity—the chemical reaction that spurs cell growth and appears to lead to its overexpression.

But Kaixiang Cao, Ph.D., an assistant professor of biochemistry at CWRU School of Medicine, is leading a team that challenges that assumption: They believe degrading the entire LSD1 protein—not merely short-circuiting the chemical reaction that leads to its overexpression—can lead to far greater success in slowing or stopping cancer growth in stem cells.

Cao said that stopping catalysis might prohibit overexpression 15% of the time, but his team’s approach has a success rate closer to 80%.

“Our findings really challenge the current paradigm,” Cao said of their research, which appeared in Nature Communications in August. “If we can develop a degrader of LSD1, we can help the patient go through less therapy—even if we cannot completely cure cancer.”

​​Why people with Alzheimer’s disease lose their defense against brain corrosion

Studies have long shown that oxidative stress corrodes the brain, leading to oxidative damage—a main indicator of Alzheimer’s disease and other related dementias. But new research, published in PNAS and led by David E. Kang, Ph.D., the Howard T. Karsner Professor in Pathology at Case Western Reserve University School of Medicine, identified why people with AD lose this so-called “oxidative damage Defense.”

A protein called nuclear factor erythroid 2-related factor 2 (Nrf2) is regularly activated in response to oxidative stress to protect the brain from oxidative damage. But in the brain of someone with AD, Nrf2 defense against oxidative stress declines.

Kang’s research found a protein called Slingshot Homolog-1, or SSH1, stops Nrf2 from carrying out its protective biological activity.

Genetically eliminating SSH1 increases Nrf2 activation and slows the development of oxidative damage and the buildup of toxic plaques and tangles in the brain—both risk factors for AD. As a result, the regular connections between brain cells are maintained and degeneration of brain nerve cells is avoided, they found. 

Case Western Reserve is among those working on SSH1 inhibitor compounds as potential neuroprotective medicines. “Many promising drug candidates are certainly in the pipeline,” Kang said.

Linking discriminatory housing practices with heart disease

In the 1930s, the United States government-sponsored Homeowners’ Loan Corp. (HOLC) established maps of neighborhoods that identified levels of mortgage risk—a practice that led to disinvestments and segregation in “redlined” neighborhoods. Now, nearly a century later, researchers still are uncovering the lasting educational, economic, and health effects of these now-illegal practices.

Among the most recent findings: U.S. military veterans who lived in these “redlined” areas had a higher risk for heart attacks and other cardiovascular issues, according to a new study by researchers at CWRU School of Medicine, University Hospitals, and the Louis Stokes Cleveland VA Medical Center. 

The study was published in the July issue of JAMA Network Open and conducted primarily by Sadeer Al-Kindi, MD, formerly an assistant professor at Case Western Reserve School of Medicine; Salil Deo, MD, an associate professor of surgery at the School of Medicine and cardiac surgeon at the VA Northeast Ohio Healthcare System; and Yakov Elgudin, MD, Ph.D., director of lung transplantation at UH Cleveland Medical Center and an associate professor of surgery at the School of Medicine.

The researchers used information from 80,000 U.S. veterans—some living, others deceased—with pre-existing cardiovascular disease who lived in census tracts color-coded by the HOLC.

They observed that, over a five-year study period, those who lived in redlined neighborhoods were 14% more likely to suffer from an adverse cardiac event like a stroke or heart attack. This effect remained even after adjusting for known cardiovascular risk factors and other social determinants of health. 

According to the researchers, their findings “underline the important fact that despite improvements in public health, access to care—and citizen health in the United States overall— significant gaps exist between communities, and progress has not been uniform across all neighborhoods.”