After surviving breast cancer, almost forty percent of female patients are affected by primary ovarian insufficiency (POI). This condition, in which ovaries don’t produce normal amounts of hormones or release eggs regularly, can result in health problems and an inability to have children. But POI isn’t caused by cancer itself—the actual culprit is DNA damage caused by radiation or chemotherapy. In the August issue of GENETICS, Rinaldi et al. report that the drug CHK2iII can preserve egg cells in mouse ovaries treated with ionizing radiation, suggesting it might one day be used to prevent POI resulting from cancer treatments.
The researchers chose CHK2iII to test because it’s an inhibitor of CHK2, an enzyme they had already showed is involved in a cell death pathway triggered by DNA damage. Their previous work indicated that deletion of the gene for CHK2 protects egg cells from dying after exposure to ionizing radiation, making them suspect that they could also protect egg cells by disabling the protein with an inhibitor like CHK2iII. Promisingly, these egg cells were capable of growing into healthy mice, implying that the DNA damage done by the ionizing radiation was repaired.
In their new study, the Rinaldi et al. demonstrate that exposing irradiated mouse ovaries to CHK2iII blocks the CHK2-mediated activation of two proteins involved in cell death after radiation exposure: TAp63 and p53. Most importantly, they showed that the same concentration range of CHK2iII also protected irradiated egg cells from dying.
To make a case for CHK2iII as a potential measure to prevent POI in women undergoing damaging cancer treatments, Rinaldi et al. had to find out whether the eggs could still be used to generate offspring. To do this, they transplanted the treated ovaries into sterile female mice. After mating, these female mice produced normal pups, indicating that the eggs were able to be ovulated and fertilized and to develop normally. More work is needed to determine whether systemic administration of this drug would also prevent fertility loss in female mice treated with radiation or other DNA-damaging cancer therapies
Although it remains to be seen whether this approach would work for humans, a method to prevent egg damage using drugs would likely avoid many of the downfalls of current fertility-preserving methods for women and girls with a cancer diagnosis. The available techniques are mainly surgical, including saving egg cells or parts of ovaries or preparing embryos via in vitro fertilization and preserving them for later. These procedures are invasive and also require patients to push back cancer treatment until they’re complete. Developing a drug to prevent POI would sidestep these problems, reducing the amount of painful procedures a patient has to undergo and allowing her to start treatment for her cancer immediately—increasing her quality of life and maybe even her chance of survival.
CITATION:
Rinaldi, V.; Hsieh, K.; Munroe, R.; Bolcun-Filas, E.; Schimenti, J. Pharmacological Inhibition of the DNA Damage Checkpoint Prevents Radiation-Induced Oocyte Death.
GENETICS, 206(4), 1823-1828.
DOI: 10.1534/genetics.117.203455
http://www.genetics.org/content/206/4/1823
Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.
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