Few scientists can claim to work full-time on both improving cancer treatment and countering the effects of bioterrorism, but Subhrajit Saha can.
Saha, Ph.D., is an associate professor and director of basic science research in the Department of Radiation Oncology at the University of Kansas Medical Center. He has spent the last decade trying to figure out how to lessen the damage that radiation therapy causes to normal tissues that are in the path of X-ray beams targeting malignant tumors. What he and his colleagues learn by solving these biological mysteries can also be applied to help those injured by radiation exposure in the event of a nuclear accident, missile or bioterrorism.
“Science has this advantage that if you allow your knowledge to think outside the box, it can find new problems to solve,” said Saha, who is also part of the Cancer Center’s cancer biology program. University of Kansas.
A fundamental question
In the summer of 2022, Saha’s lab at KU Medical Center, along with collaborators from Children’s Mercy and St. Louis University, received a five-year grant of nearly $3.6 million from the Program of Countermeasures against Radiation and Nuclear Countermeasures (RNCP) of the National Institute. allergies and infectious diseases. NIAID is the lead institute within the National Institutes of Health for the development of medical countermeasures to mitigate and treat radiation injury. This is the second consecutive RNCP grant for their lab, and they are the only research group in Kansas conducting a federally funded research program to develop a radiation countermeasure.
Radiation therapy, which causes DNA to break and cells to die, is much more effective than chemotherapy in treating some types of cancer. Nevertheless, certain parts of the body, such as the gastrointestinal (GI) tract, are particularly susceptible to radiation toxicity and injury. The cells of the gastrointestinal tract often renew themselves, which means that the cells divide often, which makes the intestines sensitive to radiation and more vulnerable to injury.
Organs such as the intestines are difficult to avoid when treating someone with pancreatic or liver cancer. The result for patients is nausea, diarrhea, vomiting and abdominal pain. The impact of radiation-induced gastrointestinal damage for victims of a nuclear explosion is even greater; it can cause sepsis and death within days.
There are no FDA-approved drugs to prevent or alleviate these injuries.
“It’s also painful for clinicians, because we want to treat [cancer patients] with our maximum dose [of radiation], and we can’t,” Saha noted. “So it’s a fundamental question – how can we protect these organs without compromising the treatment itself?”
An evil Pac-Man
The researchers hope that this new grant will help them find a strategy to mitigate radiological damage, in particular by preventing a particular type of macrophage from entering the tissues targeted by cancer radiotherapy. Macrophages, sometimes called the Pac-Men of the immune system, are white blood cells that engulf cellular debris while releasing a variety of helpful proteins.
In 2016, Saha’s lab discovered that macrophages can also help repair and regenerate radiation-damaged organs by providing proteins that stimulate cell proliferation and growth.
But not all macrophages are the same. They are all cells of the same type, but they can acquire different functions. “It’s kind of like you’re the same person when it’s 45 degrees and you’re wearing a jacket like you are in the summer when you’re wearing a t-shirt,” Saha said. “But your actions change when you change your outfit. The same thing happens with these macrophages.
The type of macrophage that Saha’s lab will attempt to block is an inflammatory variety, which is primarily derived from inflammatory white blood cells called monocytes. These inflammatory cells do the opposite of what is needed for radiation injury: they make the injury worse. Saha and his colleagues want to block the recruitment of circulating inflammatory monocytes into damaged tissues by inhibiting their interaction with chemokines, biological chemicals released by the same tissue.
A primary objective
They plan to block it in two different ways, both using a mouse model. First, they will use gene editing to abolish chemokine receptors on the surface of inflammatory cells. In response to radiation, these receptors promote the recruitment of inflammatory cells into damaged tissues. Second, they will try to use a drug compound, which is already in clinical trials for another type of cancer treatment, to inhibit the interaction of chemokines with these receptors.
“If we do not allow the recruitment of these [inflammatory monocytes] to target tissue, such as the intestine, we can inhibit inflammation and alleviate radiation damage,” Saha said. “So we can help the repair process.”
Unlike acute radiation injuries such as these intestines, which show up in just a few days, lung injuries in patients being treated for breast or lung cancer can take almost six months to develop. The researchers plan to examine how their experiments also affect the repair process of these chronic radiation injuries.
And what they learn in the lab to improve cancer care at the clinic could be used in a mass disaster or terrorist situation, a concern that has been growing since 9/11, although Saha said that he hopes his work remains confined to the clinic.
“We don’t want a potential treatment to be needed for this scenario because nobody wants there to be a nuclear accident,” he said. “Radiation was discovered for the benefit of mankind, not to destroy mankind. What we really hope is that we can bring this knowledge to the improvement of radiation therapy in several types of cancer. the primary objective.
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