Wise, professor in the UofL Department of Pharmacology and Toxicology, now has received $6.7 million over eight years from the National Institute of Environmental Health Sciences through the Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program to investigate how chromosome instability resulting from exposure to metals leads to lung cancer.

Lung cancer is the leading cause of cancer death in the U.S., and Kentucky has the highest rates of lung cancer incidence and mortality of any state. Despite the widely held perception that lung cancer is simply attributed to smoking, 1 in 5 women and 1 in 12 men who develop lung cancer never smoked. In addition to high rates of cancer, lung cancer has a five-year survival rate of 21%, one of the lowest of any cancer site.

“Lung cancer has a substantial impact on human health, particularly here in Kentucky, and it is time the misconception that smoking is the only cause of lung cancer is dispelled,” said UofL interim president Lori Stewart Gonzalez. “We are grateful for the institute’s confidence in Dr. Wise and our university to lead this work in addressing such a significant health concern. I am excited to see this amazing research continue and expand at UofL thanks to this grant.”

Metals are some of the top environmental causes of human lung cancer, but scientists do not fully understand how the metals cause cancer. Wise’s research has shown that one such metal, hexavalent chromium, causes chromosome instability, in which the chromosomes are increased, deleted or rearranged in inappropriate ways. This chromosome instability can lead to the development of cancer.

Wise has studied metals-induced chromosome instability in humans and animals. Through his field work in sampling skin and blubber from whales, Wise has discovered that while the animals are exposed to hexavalent chromium in the ocean, it results in much less chromosome instability and cancer.

“What’s thought to underlie that is a double-strand break in the DNA helix. In human and whale cells, chromium induces the same number of breaks, so you would expect the same amount of effect on the chromosomes, but you don’t see that,” Wise said. “One of the things we’ve found is that chromium also inhibits the repair of these breaks in humans – you get the breaks and you can’t fix them. In whale cells you get the breaks, but you can fix them. What about whales is protective or corrective? That’s what we’re digging into.”

Wise has assembled a team of researchers from around the world to investigate this process further with the hope that this knowledge ultimately will lead to ways of preventing and reversing metals-induced lung cancer in people.

The research will include laboratory studies and then translate those findings to wildlife and human populations of workers exposed to metals. In addition to Wise, project researchers include KeJian Liu of the University of New Mexico, who will lead lab studies and Tongzhang Zeng of Brown University, who will lead work with human populations. Doctoral students in Wise’s lab and UofL faculty members Sandra Wise, Michael Merchant and Matt Cave also will participate, along with additional researchers in the U.S., Germany, China and Japan.

“UofL is one of the top institutions in the country in research and discovery for how human health is influenced by our environment, and preeminent researchers like Dr. Wise are the reason,” said Kevin Gardner, UofL executive vice president of research and innovation. “This grant is recognition of the incredible contributions Dr. Wise has made to the field and provides ongoing support for continued discovery for years to come.”

RIVER grants are awarded to select investigators who have shown a broad vision and potential for impactful research. They allow the investigator increased flexibility and the freedom to set specific research goals toward a given objective, adjusting the research based on new findings, without seeking new funding. Cave received a RIVER grant in 2017 to conduct research into the effects of environmental exposures on fatty liver disease.

This research is built on 20 years of previous support from the NIEHS as well as seed funding from the Kentucky Lung Cancer Research program and the Jewish Heritage Fund for Excellence.

“In environmental health, the study of liver disease is relatively new, particularly in the field of endocrine disrupting chemicals,” said Cave, associate professor of medicine in gastroenterology at the University of Louisville School of Medicine. “These chemicals, such as bisphenol-A (BPA), found in plastic drink bottles, may cause endocrine and metabolic diseases like diabetes and obesity, or make them worse.” 

With the NIEHS award, Cave plans to explore how any number of endocrine disrupting chemicals contribute to fatty liver disease. The flexible nature of the award allows him to redirect the research over the course of the funding, and adapt the work in light of new leads.

Cave is one of eight environmental health scientists receiving the new Revolutionizing Innovative, Visionary Environmental health Research (RIVER) Outstanding Investigator Award from the NIEHS. Awardees were selected based on their record of innovative and impactful research. Cave’s 8-year funding is the maximum awarded for this program. The new RIVER awards differ from the NIH’s traditional approach of funding projects designed to study specific aims, which can steadily produce new knowledge but may limit scientists when their results suggest new directions. Through RIVER, Cave will be able to explore novel directions of research in environmental liver disease.

“The RIVER program is designed to fund people, not projects. It gives outstanding environmental health scientists stable funding, time, and importantly, flexibility to pursue creative scientific ideas, rather than constantly writing grants to support their research programs,” said David Balshaw, PhD, chief of the NIEHS Exposure, Response and Technology Branch who leads the NIEHS team overseeing this initiative.

“This funding mechanism gives us the flexibility to study this evolving field and the freedom to pursue the hot leads as they develop,” Cave said. “I am very flattered to receive this award. It demonstrates the confidence the NIEHS has in my work.”

While the specific projects will evolve over time, Cave’s initial work will focus on exposures to polychlorinated biphenyls (PCBs) and vinyl chloride. PCBs are chemical compounds previously used in electrical equipment and other products. Although banned from production in 1979, PCBs do not readily break down and can remain in the environment. Vinyl chloride is used in the production of polyvinyl chloride (PVC), from which plastic pipes and other construction materials are formed. Both compounds are known to cause liver damage. Cave plans a multi-tiered research approach, beginning with cell cultures and animal models and then in humans.

As a framework for his research, Cave will establish the Environmental Liver Disease Revolutionizing Innovative, Visionary Environmental Health Research Program (ELD-RIVER), a unique integrative and collaborative research program including collaborations with academia, government agencies, industry, and scientific/medical societies. Cave and award co-investigator Juliane Beier Arteel, Ph.D., are collaborating with UofL’s NIAAA Alcohol Research Center, Diabetes and Obesity Center, and researchers in cardiology, biochemistry, pharmacology and toxicology, as well as the Environmental Protection Agency.

More information about Cave’s grant is below: