Could a prostate cancer drug save lives from the deadly radiation of a nuclear blast?
That’s an open question now thanks to the results of a new study using a hormone-blocking drug called degarelix (Firmagon) to save the lives of mice exposed to a deadly level of radiation. The team’s research showed that more than two-thirds of their male mice survived after they received one dose of the approved cancer drug 24 hours after radiation exposure. In comparison, almost all irradiated mice who did not receive the drug died within three weeks due to irreversible damage to their bone marrow, which supplies the body with blood and immune cells—a “very striking difference,” said study co-leader Enrico Velardi, PhD, of Memorial Sloan Kettering Cancer Center.
Now that the group’s data are published, the team hopes to work with U.S. government authorities and the drug manufacturer on the necessary follow-up research to establish degarelix as a lifesaving treatment for people exposed to high levels of radiation, said study co-leader Jarrod Dudakov, PhD , of Fred Hutchinson Cancer Research Center. If it proves itself, he said, the drug could even be included in national disaster-emergency stockpiles.
“I’m really hopeful that this is going to be a good thing,” said Dudakov, a clinical researcher at Fred Hutch. “This is the beauty of this—especially in radiation injury—that this is an approved drug.”
The study showed that although the drug helped radiation-exposed female mice as well, unfortunately the lifesaving effect of the drug was much less dramatic than it was in the male mice. The researchers suspect that this is due to its ripple effects on the body’s supply of estrogen, which is necessary for healthy bone marrow. They’re now working to understand this discrepancy between the sexes and, hopefully, develop a way to fix it.
The researchers say that their method also could have potential to help protect patients from the damaging effects of radiation used as a cancer therapy, or other marrow-damaging therapies like chemo.
The paper was published Monday in the journal Nature Medicine. Velardi and Dudakov co-led the study with Dr. Marcel van den Brink of Sloan Kettering. It was funded by the National Institutes of Health, the research-funding agency of the European Union, private foundations and private donors.
Finding new ways to prepare for the worst
The unthinkable devastation unleashed in 1945 in Hiroshima and Nagasaki killed roughly 200,000 in the two cities during the immediate aftermath. Contemporary reports say that most of the deaths were from burns, but many resulted from the effects of radiation on bone marrow. In the years since, about 400 additional people around the world have suffered acute radiation sickness as a result of nuclear accident, according to international databases. The biggest group of them was at Chernobyl, where 134 people grew ill from radiation in the days after the Soviet nuclear reactor exploded in 1986 and 28 died of bone marrow failure shortly thereafter.
A high dose of radiation in a short amount of time kills off the sensitive cells of the marrow and the bloodstream, putting patients at risk for infection due to loss of white blood cells and uncontrolled bleeding from the loss of blood-clotting platelets.
Certain drugs that stimulate the development of blood cells are approved to treat acute radiation sickness because animal studies have shown that they boost survival after radiation exposure. Supportive care, like blood infusions and antibiotics, also help improve survival, research shows. Through its disaster-preparedness authorities, the federal government is supporting the development of several different potential strategies to save lives from acute radiation injury. But transplanting the bone marrow cells of a healthy donor—a highly specialized medical procedure that certainly wouldn’t be made easier by the sudden chaos of a mass incident—is the only curative therapy with the potential to save the life of someone with the most severe, irreversible level of marrow damage from radiation.
“Transplant for all these people is not a feasible approach. You’ll fail to find the donors; you’re not going to be able to get the cells,” Dudakov said. “So there’s a real need for these non-cellular approaches to promote survival after radiation injury.”
Approved for the U.S. market in 2008, degarelix is a powder that’s mixed with water for injection under the skin. It acts on a hormonal pathway through which the brain signals the gonads (testes or ovaries) to make the sex hormones testosterone and estrogen. The drug blocks a key trigger near the beginning of the pathway; the eventual result is a temporary, pharmacological castration as production of the sex hormones plummets.
Blocking sex hormones is an important treatment for certain cancers, especially prostate cancer, for which this drug is approved. Because testosterone fuels the growth of prostate tumors, many different drug treatments have been developed to treat advanced prostate cancers by interfering with the production or uptake of the hormone. Sex hormone–blocking treatments are also used in advanced breast and ovarian cancers.
Earlier research, including work by Dudakov and his collaborators, had shown that blocking sex hormones promotes the regeneration of the immune system after damage to the bone marrow. The most common drugs used in the clinic for blocking the production of these hormones, however, first cause a surge of sex hormones before turning off the spigot. Degarelix works in a different way and doesn’t cause a surge, so the research team thought it could be better for helping boost survival after dangerous radiation injury—when a fast, immediate response is necessary.
The researchers ran their mouse experiments half a dozen times and the result was consistent—a dramatic difference in survival among male mice who received one dose of degarelix one day after an almost-universally lethal dose of radiation (about 70 percent survival with degarelix compared to about 5 percent survival without). Additional doses of the drug didn’t do anything more, the team found—one was the magic number. And if they delayed giving the drug one more day, it still saved lives (just not quite as many).
The researchers hope to pursue additional studies that would help build the case for this drug’s potential in helping mitigate disaster in a nuclear emergency. Obviously randomized tests of the drug’s potential to save human lives from radiation damage are out of the question for ethical reasons. But additional lab-model studies, plus studies of blood-forming cells in patients prescribed this type of drug as a cancer treatment, may help build the case, the researchers said.
The drug works in an unexpected way
Perhaps the biggest surprise for the researchers was not that the drug worked, but how it worked. They found that the protective mechanism of the drug wasn’t due to the drop in sex hormones at the very end of the Rube Goldberg-like signaling pathway it triggers. Rather, it was one of the intermediate players along the way, which they discovered to have a direct effect on the most primitive of the blood-forming stem cells in bone marrow—an effect that previous studies had only hinted at.
The intermediate player is called luteinizing hormone, and it is produced by the pituitary gland in response to a signal sent from another gland in the brain. Its main known job is to travel through the bloodstream to the gonads to trigger sex-hormone production. (Among non-medical people, luteinizing hormone is probably best-known to women who have ever used a home ovulation test—the test looks for the surge in luteinizing hormone levels that signals peak fertility.)
The team found, unexpectedly, that key blood stem cells are covered with receptors for luteinizing hormone. And, what’s more, their experiments with Fred Hutch stem-cell expert Hans-Peter Kiem, MD, PhD, uncovered that the hormone stimulates the cells to multiply (exactly how, the scientists still don’t know). So when luteinizing hormone was taken away via treatment with degarelix in the researchers’ experiments, the few blood stem cells that survived the blast of radiation went into a resting state temporarily.
This likely gave the cells a chance to repair the damage the radiation had caused before activating to regenerate the blood and marrow cells that had died, the researchers speculated.
“If you promote quiescence in the stem cells, leading them not to proliferate, early after radiation, that is actually a beneficial thing,” Dudakov said.
“This was very fascinating, because historically this hormone has been studied in the regulation of sex hormones, with the receptor mainly expressed by the cells of gonads,” Velardi said. “So this really caught our interest.”
This surprise is now opening up an additional area of investigation, besides the team’s ongoing efforts to develop this drug as a treatment for radiation injury: With Fred Hutch colleague Kiem, Dudakov is now working to see whether this property of luteinizing hormone could make it a good laboratory tool for multiplying key blood stem cells used in therapies for cancer or other serious diseases.
This article was originally published on January 9, 2018, by Hutch News. It is republished with permission.