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 .

Building on more than two decades of success in cancer research, the University of Louisville is poised to advance immunotherapy with a grant of $11.5 million from the National Institute of General Medical Sciences to establish the (CCII). The new center will develop and improve strategies that use the immune response to fight cancer. The five-year grant also will allow UofL to establish the CCII as a National Institutes of Health-designated Center of Biomedical Research Excellence (CoBRE) to support young investigators and develop additional basic, translational and clinical research at the .

“One of the university’s Grand Challenges is to advance the health of all people,” said UofL President Neeli Bendapudi. “Through this center, our cancer researchers will grow the field of immunotherapy, saving the lives of many more patients with cancer in the future.”

“Our mission is to harness the power of the immune system to eradicate cancer,” said Jason Chesney, director of the Brown Cancer Center. “The University of Louisville, UofL Health and the Brown Cancer Center have been at the forefront of the clinical development of a new generation of immunotherapies that have been proven to increase the survival of cancer patients. This grant from the federal government leverages our existing strengths in cancer immunology and clinical trials to accelerate the development of new immunotherapies that will translate into lives saved across the globe.”

Cancer survivor Jeff Habermel received two different immunotherapies at Brown Cancer Center in the course of treatment for three different cancers, including metastasized melanoma.

“I consider myself very fortunate to have the type of care that Dr. Chesney and Dr. (Donald) Miller and the whole staff provide at the Brown Cancer Center. We have a world-class facility right in our backyard,” Habermel said. “I truly feel I am the luckiest man in the world to live in a time when we have such technologies and such amazing abilities to treat cancer in these ways.”

The newest cancer treatments often are available at Brown Cancer Center through clinical trials before they are available anywhere else. One such treatment is CAR T-cell therapy, in which a patient’s own immune cells known as T cells are modified in the lab to more effectively attack cancer cells. UofL announced the creation of the at UofL in October.

“Our leading-edge cancer program improves access for patients in our region, giving them the opportunity to benefit from life-saving immunotherapies through clinical trials,” said Tom Miller, CEO of UofL Health. “Thousands of our cancer patients – our neighbors and family members – are alive today because of this early focus on drugs that activate immunity against cancer.”

Researchers within the CCII will build on expertise and resources gained from previous research at UofL to develop better cancer immunotherapies. This will be achieved in part by enabling talented junior investigators who have not yet obtained major funding to advance their research and subsequently obtain major grant awards of their own.

“One of the major goals of the center is to cultivate the next generation of cancer scientists in immunology and immunotherapy,” said Jun Yan, professor, director of the CCII and chief of the UofL Division of Immunotherapy. “Starting in year two, we will call for pilot projects that will bring in more researchers and investigators to work on immunotherapy and immunology.”

The young researchers are provided funding, mentorship and access to sophisticated facilities to advance their research. Once CCII-supported researchers obtain their own funding they rotate out, allowing new investigators to come in to the program.

“It’s training a cohort of new investigators who will have their own large grants and expertise,” said Paula Bates, professor of medicine and co-investigator for the CCII along with John Trent. “We are building a critical mass of well-funded researchers in the area.”

Senior UofL faculty members Robert Mitchell, Nejat Egilmez, Haribabu Bodduluri, Huang-Ge Zhang and Bing Li will serve as mentors and core directors for the CCII. In the first year of the program, four junior researchers at UofL are conducting projects to improve the effectiveness of immune therapies.

• Chuanlin Ding is investigating the impact of chemotherapy on anti-tumor immunity in breast cancer order to discover effective combination regimens that improve conventional chemotherapy.
• Qingsheng Li is exploring a method to improve immune checkpoint inhibitor therapy for non-small cell lung cancer. Immune checkpoint inhibitors are a type of immunotherapy that blocks proteins (checkpoints) made by immune system cells, such as T cells. The checkpoints can prevent T cells from attacking cancer cells.
• Corey Watson is studying immune cells to determine which of these cells are beneficial to lung cancer patient outcomes and how they may help kill tumor cells.
• Kavitha Yaddanapuddi is studying immune checkpoint inhibitor resistance in lung cancer patients. This will help in developing therapies that reduce resistance and improve treatment.

This grant may be extended for two additional five-year phases. A previous CoBRE program for cancer research at UofL was extended through all three phases, lasting 15 years. That program significantly expanded the contingent of both junior and senior investigators at UofL, including Chesney, Trent and others whose research was funded by the previous program.

“This type of funding has been truly transformative for this cancer center,” Trent said. “The research for the current generation of immunotherapeutic checkpoint inhibitors was done more than 18 years ago. This grant’s research will feed into the clinical work in time. These grants lay the groundwork for the next generation of therapies.”

To extend the impact of the CCII still further, Kosair Charities has provided an additional $200,000 to facilitate the discovery and development of immunotherapy drugs for children with cancer. This gift bridges the CCII and the UofL Kosair Charities Pediatric Oncology Research Program, allowing the CCII to focus also on immuno-oncology for children.

“Kosair Charities is proud to be the first community partner to support the UofL Center for Cancer Immunology and Immunotherapy,” said Kosair Charities President Keith Inman. “The UofL Kosair Charities Pediatric Cancer Research Program will allow this new center to include crucial pediatric cancer research as well as expand the scope to all people living with cancer – children and adults alike.”

Qualigen Therapeutics Inc., a California biotechnology company focused on developing novel therapeutics for the treatment of cancer and infectious diseases, has signed a license agreement for the technology and plans to fund continued development with UofL to ready it for market.

The technology works by targeting the RAS protein, which sends signals that regulate when and where the body produces and grows new cells. When mutated, the protein turns into a “stuck accelerator pedal,” according to UofL researcher Geoffrey Clark, who co-invented the technology with colleagues John Trent and Joe Burlison.

“Normally, it gets pressed when you need to grow and then the foot comes off and the cell slows down,” said Clark, professor of pharmacology and toxicology at UofL. “When it becomes mutated, the accelerator’s jammed on, with cells continuing to grow and ultimately becoming a cancerous tumor.”

The drug targets only the active RAS protein and, so far, has little toxic effect on healthy cells. Many current non-targeted treatments, such as chemotherapy, can hurt both healthy and cancerous cells, leading to painful side effects. By some estimates, targeting this mutation could stop the growth of at least a third of human tumors.

“The patient impact could be extremely broad because RAS is involved in a lot of different cancers,” Trent said. “It’s one of the holy grails that there has been limited success in targeting.”

Trent leads the Molecular Modeling Facility at UofL Health – James Graham Brown Cancer Center and the UofL partnership with , a non-profit with a network of school computers across the state. When the computers aren’t being used by students, they’re connected to act as a distributed supercomputer, allowing researchers to process and analyze huge amounts of data.

Trent used that capability to run through millions of cancer-fighting drug possibilities in a matter of days. The result was a drug that could inhibit the deregulated RAS protein.��Development of the technology was supported by the UofL NIH REACH ExCITE program.

Qualigen holds an exclusive license to the technology through the��, which works with startups and industry to commercialize university-owned technologies. This license agreement builds on a sponsored research agreement with Qualigen for the development of several small-molecule RAS Inhibitor drug candidates. Qualigen also has licensed and is developing other UofL technologies for fighting COVID-19 and .

“Partnering on this new cancer-fighting technology is another example of the relationship we’ve developed with the University of Louisville,” said Michael Poirier, CEO of Qualigen. “We look forward to working with UofL and to advancing this important clinical program with the goal of developing an effective treatment for this unmet need.”

More information about supporting this cancer research at UofL is available online.����

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.

“Innovation is absolutely critical to the University of Louisville’s mission,” said UofL President, Neeli Bendapudi. “It’s what drives us, inspires us, and it’s a big part of what makes us a great place to learn, work and invest — our three most important goals as a university.”��

The event, hosted by the and the honored UofL innovators who had recently been awarded a patent or whose technology had been licensed to a company for commercialization.��

“Our researchers and innovators do tremendous work with the power to change and improve lives,” said Allen Morris, executive director of the Commercialization EPI-Center, formerly the Office of Technology Transfer. “That’s what this event is about — celebrating them, and the work they do.”

Two large awards were also presented: Susan Ildstad was given the Innovator of the Year Award and John O. Trent was given the Career Impact Award. Each took home a red-and-black glass flame — the symbol for the event.��

Ildstad’s company, Talaris, recently to develop a therapy invented at UofL that could improve the lives of kidney transplant recipients. The technology, which just entered its phase three clinical trials, could allow living donor kidney transplant recipients to stay off immunosuppression drugs, which they would otherwise need for the rest of their lives.

Likewise, Trent has a long a history of collaborating on technologies, particularly in . Some of his notable inventions include AS1411, novel PFK inhibitors for fighting the spread of cancer and his natural product hand cream for DNA repair, now licensed to and in clinical development by Repairogen.��

Robert S. Keynton, interim executive vice president for Research and Innovation, said this year has been a at UofL. In 2019, he said, UofL saw more research disclosures of new innovations, more commercialization deals and more innovation income.

Keynton also noted several success stories that had gained attention over the past year: One team, he said, developed a new method of , extending its shelf life for the battlefield, rural areas and even space travel. Another team developed a way to , which could have huge impacts for our environment. And yet another is helping people .

“The work you do is significant,” he said. “The work you do is important. The work you do has impact. And I’m proud to be part of it, both as the Interim EVPRI and as an inventor myself.”

Check out some of our innovators:��