The UofL team, led by John O. Trent, professor of medicine and deputy director of basic and translational research at the Brown Cancer Center and Jonathan B. Chaires, professor of medicine, used the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory near Chicago, to define and model the longer genetic sequence structures that are believed to be the source of changes that mutate healthy cells into cancer cells.

Previous methods limited most studies to strings of fewer than 33 nucleotides. The new model developed by the UofL team enables researchers to study sequences of up to 70 nucleotides, which may provide more accurate targets for drug intervention.

By combining multiple processes, the team developed models of the G4 quadruplex structures that can be used in computer analysis to virtually test how drug and disease molecules might interact with these sites before real-world testing in the lab. This testing may aid in the discovery of drugs that could inhibit the mutation process for oncogenes c-Myc, c-Kit and k-Ras, which are associated with lung, pancreatic, colon and other cancers.

“Using integrative structural biology, we can determine that these oncogene promoters can form unique, complicated higher-order structures. We can use these structures for discovering specific inhibitors to stop gene transcription at the DNA level without nonspecific DNA-binding side effects,” Trent said. “This opens up targeting DNA by therapeutics like we target proteins.”

The research to develop the model was published in earlier this year. A profile of the team’s work has been  and will be featured in their annual report later this year.

The team now has begun using this structural understanding and the new models in ongoing anti-cancer drug discovery work, which includes data processing using the combined power of computers located in K-12 schools across Kentucky. The dual-purpose computer grid is a partnership with Dataseam, established in 2003 and funded by the Kentucky General Assembly to provide computing infrastructure, workforce development and educational opportunities for students and staff in Kentucky school districts.

Fellows are selected for their “spirit of innovation” in university research, helping to generate groundbreaking inventions that have a tangible impact on quality of life, economic development and the welfare of society.

Trent is the only 2020 fellow from the state of Kentucky and the seventh from UofL. The 2020 Fellow class of 175 inventors represents 115 research universities and governmental and non-profit research institutes worldwide.

“It’s certainly an honor and I think it’s a testament to the drug discovery program we’ve built at the Brown Cancer Center and UofL through many collaborations and partnerships,” said Trent, a professor of medicine and the Wendell Cherry Endowed Chair in Cancer Translational Research. “The benefits of UofL are the support we’ve had for taking creative activities through intellectual property protection to the commercialization grant programs.”

As deputy director of basic and translational research at the , Trent’s Molecular Modeling Facility uses computer predictions to understand and virtually test how drug and disease molecules might interact before real-world testing in the lab.

Trent also runs the UofL partnership with , a company that created a grid that uses the processing power of thousands of computers in schools across Kentucky that Trent uses to screen potential drugs and compounds against and, most recently, . The DataseamGrid has the capability to screen millions of potential compounds against molecular targets in only a few days.

Trent holds more than 50 patents, 24 of which are U.S., and numerous licenses and option agreements with potential commercial partners. Among other accolades, he received the Apple Science Innovator Award and the 2019 , the latter awarded through the UofL Commercialization EPI-Center.

“We’re very proud of John, and all his work to create innovations that have the power to advance our health,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “The fact that John and other UofL researchers before him have received this honor, the highest for academic inventors, shows our university’s commitment and leadership in research, invention and developing technologies that change and improve the way we work and live.”

Previous Fellows from UofL include Suzanne Ildstad and Kevin Walsh (2014), William Pierce (2015), Paula Bates (2016), Robert S. Keynton (2017) and Ayman El Baz (2019).

Trent’s induction, paired with Bates’ four years earlier, also makes the two of them one of only a handful of married couples to be named fellows. The duo also frequently works together, including developing the aptamer that would become the basis for innovative technologies since applied to fight and novel .

The 2020 NAI Fellow class collectively holds more than 4,700 issued U.S. patents.

Among the class are 24 recipients of National Academies of Sciences, Engineering, and Medicine honors, six recipients of American Academy of Arts & Sciences honors and two Nobel Laureates, as well as other honors and distinctions. The complete list of 2020 NAI Fellows is available .

The desktop computers are part of the DataseamGrid, a network of computers housed in classrooms of 48 Kentucky school districts as part of a partnership designed to support research, education and workforce development.

John Trent, PhD, deputy director of basic and translational research at the , conducts virtual screening to discover new cancer drugs using the DataseamGrid for high-volume computations. Today, he has the computers at work 24/7 to identify the most promising drugs and compounds to fight SARS-CoV-2 and its disease, COVID-19.

“In these unprecedented times, we had a resource where we could potentially make an impact quickly and switch over from some of our cancer targets to SARS-CoV-2 targets,” Trent said. “We have been very successful in doing this in cancer for 15 years. We are using the same approach in targeting the coronavirus, just targeting a different protein.”

Established in 2003, is funded by the Kentucky General Assembly to provide computing infrastructure, workforce development and educational opportunities for students and staff in Kentucky school districts. Available computing power in those units is put to work performing computer modeling calculations to screen anti-cancer drugs for Trent’s team and collaborators at UofL.

“Like a lot of industries, we have shifted our skills and infrastructure to address this issue,” said Brian Gupton, CEO of Dataseam. “We are always going to have cancer, but at least for the time being, we are glad the DataseamGrid is here for Dr. Trent to screen those drugs.”

In mid-March, Trent and his team entered new data onto the DataseamGrid, along with UofL’s dedicated research computers, in a two-pronged approach to match three-dimensional models of proteins in SARS-CoV-2 to drugs and compounds that could help in treating or preventing COVID-19. The DataseamGrid provides up to 80 percent of the computational power for these projects.

The first approach is to test about 2,000 drugs already on the market and another 9,000 investigational drugs and nutraceuticals that have been tested for toxicity to isolate those most likely to be effective against the virus.

“For the immediate approach, we are testing drugs that already are approved by the FDA or have been tested in humans. If we find activity with those drugs, we could get them into patient trials a lot quicker,” Trent said. “However, these drugs obviously were designed for something else and they may not have the same efficacy of a very selective drug.”

To find that selective drug, Trent’s second prong of research includes computational models to screen 37 million small molecules and compounds against the target proteins in SARS-CoV-2. These molecules could be used to develop a new drug specifically to treat the virus. That process would take more time, however, to obtain FDA approval.

“That initial discovery of a new, more-selective agent is more long term. You are looking at 12 to 18 months before you would even think about testing those in a patient,” Trent said. “But time is of essence at the moment, so we are doing both things at the same time.”

Using the DataseamGrid and UofL research computers, Trent and his team are screening the drugs and small molecules against 3-D structures of four proteins in the virus to see which compounds might bind with the proteins. A drug that interferes with the activity of any of these proteins would reduce the virus’s ability to spread.

Trent began the research with the first two proteins described for SARS-CoV-2: the main protease, an essential enzyme used by the virus to break down viral proteins and make new virus particles, and spike proteins, the triangular “knobs” the virus uses to attach itself to host cells. These spikes are the knobs commonly seen in graphic images on the surface of the virus. Trent now also is testing drugs against two additional target proteins that were described very recently.

So far, the process has identified about 30 drugs as potentially effective against SARS-CoV-2. Trent recommended these for biological testing by other UofL researchers in the (CPM). Directed by Kenneth Palmer, Ph.D., the CPM is one of only a few labs in the United States capable of testing the drugs against the virus. That testing is expected to begin in mid-April.

If the CPM researchers find the drugs to be effective against SARS-CoV-2 in the lab, they could be moved to the next phase of testing in animal models, testing that also may be conducted at CPM.

“This computer modeling is an excellent way to identify the best potential candidates for laboratory testing rapidly, and this strategy could lead to relief sooner rather than later for patients suffering from COVID-19,” Palmer said.

Gupton says it is good to know the DataseamGrid continues to support urgent medical research even though students are working from home.

“Ironically, we hope to return to cancer research as soon as possible,” Gupton said. “Even though the students are not in classrooms, Kentucky school districts are providing them with instruction, technology, internet access and even meals. The districts’ Dataseam systems engineers are supporting both the university’s work and K-12 efforts. We all are proud to be ‘digital first responders’ in Kentucky’s part of the global fight.”

As part of the Dataseam partnership, UofL provides academic scholarships annually for students from participating school districts who come to the university to pursue a degree in science, technology, engineering or math.

The UofL technology works by targeting the RAS protein. When mutated, RAS turns into a stuck accelerator pedal, says Dr. Geoffrey J. Clark, a co-inventor of the technology.

“Normally, it gets pressed when you need to grow and then the foot comes off and the cell slows down,” said Clark, an associate professor of pharmacology and toxicology at UofL. “When it becomes mutated, the accelerator’s jammed on.”

Cells suddenly start growing very fast and don’t stop growing when they’re supposed to. They become aggressive, he said, and penetrate other tissue, just like a tumor cell.

“The argument’s always been that if we could stop this RAS protein from working, we could shut down probably at least a third of human tumors,” he said.

But that’s easier said than done. There were a lot of potential compounds to test, and no attempt before had been successful.

So, Clark enlisted fellow professor and researcher Dr. John Trent, who runs the Molecular Modeling Facility at UofL. Trent used the school’s partnership with DataSeam, a non-profit with a network of school computers across the state.

When the computers aren’t being used, they’re connected to act as a distributed supercomputer, allowing researchers to process and analyze huge amounts of data — for example, running through millions of possible drugs to combat RAS in a matter of days.

The result was a drug that could inhibit the deregulated RAS protein. 

“The patient impact could be extremely broad, because RAS is involved in a lot of different cancers,” said Trent, also a co-inventor. “It’s one of the holy grails that has just been unsuccessfully targeted until now.”

The drug targets only the active RAS protein, and so has little toxic effect on healthy cells. Current non-targeted treatments, such as chemotherapy, can hurt both healthy and cancerous cells, leading to painful side effects.

The drug was tested and optimized at the Brown Cancer Center’s Medicinal Chemistry Facility, which works with researchers to improve the drugs and eliminate any potential problems.

“Our goal is to take these initial discoveries and elaborate on them, and potentially get them into the clinic,” said Dr. Joe Burlison, the facility’s director.

Getting the drug to the clinic is crucial, they said, because that’s where it can benefit patients.

To reach that goal, the team has been working with resources around campus and within the .

The team received funding through ExCITE and other grant programs to further development, and is now working with the Office of Technology Transfer to protect the technology and find a commercial partner.