Dr. Amanda Paulovich, of the Clinical Research Division, is working to find biomarkers that could be used for a rapid point-of-care test for radiation injury. She recently received a $2.2 million, five-year award from the National Institute of Allergy and Infectious Disease to conduct the research.
The potential diagnostic test is intended to quickly screen many people for radiation-related damage in the event of a nuclear attack or accident, but could also reveal whether cancer treatments, either chemotherapy or radiation, are taking too much of a toll on a patient’s body. The test also could potentially be used as a screen to predict a person’s general risk of developing cancer.
The Paulovich Lab studies the DNA damage response pathway, a group of proteins in our cells that signals and responds when DNA is injured. Pieces of this pathway often go awry in cancer, and mutations in the pathway are found in nearly all inherited cancers.
"This pathway is exquisitely important in cancer, in everything from determining your risk in developing cancer, to determining your risk of toxicity from cancer therapies, as well as potentially determining your tumor’s response to treatments," said Paulovich. "Right now we don’t have great assays for monitoring the activity of this pathway."
The group’s interest in radiation injury evolved naturally from their work on the DNA damage pathway, said Richard Ivey, project manager in the Paulovich Lab.
"Our focus has always been on the DNA damage response, so this is a really good tie-in," he said. "We’re interested in the role of the DNA damage response in cancer, and now we’re just looking at it in the context of radiation injury."
Radiation, in the form of cancer treatment or nuclear radiation, is very damaging to DNA. This damage is responsible for radiation sickness and for toxic side effects to radiation therapy. Many chemotherapies also harm DNA.
In the event of a nuclear attack or accident, sifting out those who have received dangerous amounts of exposure from the crowd of panicked but ultimately unaffected people is next to impossible. Many cases of radiation injury are treatable if caught early enough, so emergency clinics need a rapid, easy test to triage those in immediate need of care.
In the five-year study, Paulovich’s group — in collaboration with Cyd Nourigat, of the Bernstein Lab, who maintains colonies of immunodeficient mice — will use a mouse model to hunt for protein biomarkers of radiation damage in the bone marrow, the site of the most dangerous type of radiation sickness. The mice will be fed food with a label that incorporates into their cells’ proteins and then irradiated. The researchers will use mass spectrometry to look for DNA damage response proteins in the mice’s bone marrow that are increased in the presence of radiation. Once biomarkers have been identified and validated in mice, the researchers will look for these potential radiation markers in humans, using cancer patients that are undergoing radiation therapy.
A marker that signals a person’s level of DNA damage rather than amount of radiation they received is important because people have widely varying sensitivities to radiation. Two people could be exposed to the same nuclear accident or receive the same dosage of radiation therapy and have very different levels of injury.
"It’s critically important for society to have a diagnostic like this, given the likelihood of a nuclear incident," Paulovich said.
Paulovich hopes that this project will lead to the development of tools to stratify cancer patients more sensitive to DNA damage, those who will see worse side effects from chemotherapy and radiation and could be treated with lower doses. She also envisions a screening tool to determine a person’s overall risk of developing cancer, as people more prone to DNA damage are at higher risk for cancer.