Could a Prostate Cancer Drug Save Lives From Radiation Injury?

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.