With DART, ORNL and UT researchers partner to take aim at one of deadliest cancers

In Tennessee, a state where cancer survival rates already trail the national average, ovarian cancer ranks among the deadliest.

It's extremely hard to diagnose in its early stages, can metastasize quickly into the peritoneal cavity, and is frequently resistant to chemotherapy.

That made it a perfect target for a collaborative effort among the U.S. Department of Energy's Oak Ridge National Laboratory, the University of Tennessee in Knoxville, and the UT Health Sciences Center in Memphis.

"When ovarian cancer goes metastatic, there are not really a whole lot of options," said Sandra Davern, who leads ORNL's Radioisotope Research and Development Section in the Isotope Science and Engineering Directorate. "This is a unique cancer that needs a lot of attention and is not really getting it."

A network of researchers from UT Health Science Center, UT and ORNL are collaborating on the Development and Advancement of Radiopharmaceutical Therapies (DART) initiative, one of five current convergent research initiatives of the University of Tennessee-Oak Ridge Innovation Institute (UT-ORII).

"Radiopharmaceutical therapies are one of the hottest areas of research in the field of nuclear medicine," said Gabor Tigyi, researcher at UT Health Sciences Center.

UT-ORII was created in 2021, forming a hub for world-class discovery and innovation, interdisciplinary graduate education and talent development. DART, launched in 2024, is its first convergent research initiative focused on health, with scientists from East to West Tennessee working together to propel the development of radiopharmaceutical therapies that could directly attack ovarian and other cancers. They include Davern, long a leader in the development of radiopharmaceuticals; Rachel Patton McCord, associate professor of Biochemistry & Cellular and Molecular Biology and adjunct associate professor of Genome Science and Technology at UT; and Tigyi and Junming Yue, also with Memphis's UT Health Science Center's College of Medicine, where Yue is a professor in pathology and Tigyi a Harriet Van Vleet Endowed Professor in Basic Oncology Research. Tigyi and Yue are members of Memphis's Center for Cancer Research, which has a mission to improve the health and well-being of Tennesseans and the global community by fostering integrated, collaborative and inclusive education, research, scientific discovery, clinical care and public service, specifically related to cancer.

"We anchored our proposal on the strengths we have in Tennessee, but also the problems of high cancer rates and lower outcomes," Davern said. "Together, we can potentially do something that's bigger than any one institution can do."

McCord's strengths include genomics and molecular biology - specifically, an understanding of the 3D architecture of chromosomes inside human cells, helpful when looking at the effects of radiation on cells and DNA. Misshapen nuclei are a diagnostic characteristic of cancer, and McCord's work has shown how alterations in chromosome folding inside nuclei can underlie cancer progression and metastasis.

Since the initiative was chosen for UT-ORII funding in 2024, nearly a dozen researchers have started working on it. ORNL has hired four dedicated scientists - two each in computing and isotopes - along with involving several students in related research. UT Health Sciences Center has hired three, and UT recently made its first hire. In addition, UT-ORII is hiring a Governor's Chair in Nuclear Medicine to focus on precision radiopharmaceuticals, leading high-profile research and working collaboratively with a growing network of radioisotope and radiochemistry researchers through DART. The prestigious Governor's Chair program, established in 2006, is funded by ORNL and the state of Tennessee.

One goal is to find molecules that recognize specific signatures on cancer cells. These signatures aren't present, or are present in much lower amounts, in healthy tissue. By recognizing this signature - and, by extension, which cells are cancerous - "targeting" molecules could be used to deliver radiation directly to those cancer cells. The alpha particles from the radiation irrevocably break the cancer cells' DNA strands.

Xofigo, an alpha therapy that uses the chemical properties of bone-seeking radium to treat metastatic prostate cancer, already is FDA-approved. Davern thinks more therapies using alpha radiation, which irradiate a smaller area, will soon be approved for cancer treatment.

Studies indicate the alpha therapy treatments could be effective in patients who have become resistant to beta therapy.

Yue specializes in ovarian cancer and has developed multiple cell and mouse models that have been used for preclinical drug screening and will be leveraged for testing targeted alpha therapies within the DART initiative. Tigyi has a history of work in radiation biology of radioprotective agents and development of antimetastatic and experimental treatments to boost tumor immunity, as well as experience in developing startup companies.

And Davern leads several ORNL radiotherapeutic initiatives, backed by the national lab's long expertise in radioisotope development and production, and its unique facilities, such as the High Flux Isotope Reactor (HFIR), the strongest reactor-based neutron source in the nation; the Oak Ridge Leadership Computing Facility (OLCF), a cutting-edge high-performance computing facility with some of the world's fastest supercomputers; and the Radiochemical Engineering Development Center, a facility where highly trained technicians and researchers produce rare and complex radioisotopes for a variety of missions, including medicine.

"We felt like this was a great multidisciplinary team to propose what we wanted to do," Davern said.

What they want to do, ultimately, is to find a way to consistently deliver a tailored dose of radiation directly to ovarian cancer cells in the body.

More broadly, they're focused on developing a new generation of theranostics - a combination of therapy and diagnostic imaging drugs -that use targeted alpha-emitting radioisotope constructs to precisely kill cancer cells throughout the peritoneal cavity.

"Targeted alpha therapy is uniquely suited to this disease pattern because alpha particles travel only a few cell diameters, delivering highly potent, localized DNA damage without harming nearby healthy organs," Yue said. "For patients with metastatic ovarian cancer, where therapeutic options are limited and survival rates have remained largely unchanged for decades, the promise of targeted alpha therapy represents a potential paradigm shift."

Supported by DOE's Office of Isotope R&D and Production (DOE IRP), ORNL already successfully researches and produces isotopes for medical purposes - notably, actinium-225, in demand for clinical trials around the world, and actinium-227, the critical raw material for the radium-223 used in an FDA-approved treatment for prostate cancer that has metastasized to bone. The lab also funds a five-year initiative that allows isotope researchers to explore radiopharmaceutical therapies with different collaborators across ORNL, including in chemical sciences, biological sciences and computational sciences.

The DART initiative seeks to establish the education framework and workforce pipeline needed to attract radiopharmaceutical companies to Tennessee for a "Radiopharmaceutical Corridor." Ultimately, this would drive economic growth, by integrating research and production, while also advancing radiopharmaceuticals as a frontline technology for cancer treatment.

Davern said the Radiopharmaceutical Corridor aligns well with Gov. Bill Lee's goal of advancing nuclear for energy in Tennessee.

"The workforce that we can build around radiopharmaceutical development and radioisotope production aligns quite well with the workforce that is required for nuclear energy," she said.

In addition, two approved targeted therapies use beta radiation: Pluvicto, for prostate cancer, and Luthathera, for neuroendocrine cancers.

Researchers have been working on developing and designing molecules that can move radiopharmaceuticals made from radium, actinium, lead and other isotopes through the body, as well as nanoparticles that can "cage" them, preventing radiation from moving beyond the treatment site.

But they're also seeking better understanding of the effects alpha emitters have on different types of cancer cells - including ovarian.

"If we can understand that now, we're at a place in time where chemotherapy was when it was first rolled out," Davern said. "And if we understood better how resistance evolves, perhaps we can be ahead of the game in mitigating strategies to prevent it."

McCord is currently working with new UT-ORII hires at UT Health Science Center to understand how 3D genome folding changes may enable ovarian cancer resistance to first-line drugs, and how understanding these changes can help identify targets for alpha therapy in drug-resistant disease.

"We know a lot about how radiation from sources like UV and X-rays impact cells and their DNA, but the type of damage caused by alpha emitters is quite different," McCord said. "Very little is known about how cells that survive the alpha radiation may respond and adapt. We are also studying what kinds of combination therapies can alter chromosome structure to further sensitize tumor cells to radiation."

Other DART research is focused on properties of cancer cells that differ from normal cells and can be used to target them; effects of isotopes on skin; developing models of ovarian cancer to use in testing; and compiling bioinformatics that can advance researchers' understanding of the cells and how different radiotherapies might affect them.

"Trying to advance these therapies for one specific disease, ovarian cancer, helps coalesce all of us around one specific goal and prove that we can be successful together," Davern added.

Davern said the collaboration won't end with the initial three institutions but is an opportunity to build a regional ecosystem to innovate cancer therapies, ultimately serving people of the state who don't have the resources to travel far and wide for treatment. She expects to pull in other hospitals and medical facilities, other universities and even private companies working in radiopharmaceuticals.

Already, Vanderbilt University Medical Center is collaborating with DART to help automate radiopharmaceutical dosing for patients.

"We are excited to work closely with Oak Ridge for the development of automated certified Good Manufacturing Practices-compliant systems to manufacture and process novel radioisotopes," said Adam Rosenberg, research associate professor in Radiology and Radiological Sciences at Vanderbilt.

Over the next decade or so, Davern envisions a nuclear-trained "smart workforce" and even, one day, a National Cancer Institute-designated Comprehensive Cancer Center in East Tennessee. Studies suggest the availability of treatment at an NCI can dramatically improve survival rates.

"We know partnerships are really important to make things happen," Davern said. "We're uniting for impact. We're tackling cancer through collaboration."

UT-Battelle manages ORNL for the Department of Energy's Office of Science, the single largest supporter of basic research in the physical sciences in the United States. The Office of Science is working to address some of the most pressing challenges of our time. For more information, please visit energy.gov/science.