For premenopausal women undergoing cancer treatment, one of the most distressing complications can be infertility. A new study describes how a class of drugs once investigated as a cancer treatment may have the potential to prevent female infertility caused by radiotherapy.
In a study of female mice, researchers found that blocking checkpoint kinase 2 (CHK2) gene activity with drugs called CHK2 inhibitors protected the rodents' oocytes, or immature eggs, against damage from radiation.
Study leader John Schimenti, of the departments of Biomedical Sciences and Molecular Biology and Genetics at Cornell University in Ithaca, NY, and colleagues recently reported their results in the journal Genetics.
Infertility is a major concern for women of reproductive age who are being treated for cancer. Both chemotherapy and radiotherapy - two of the most common cancer therapies - can destroy oocytes, making it harder for a woman to conceive, particularly after the age of 35.
Schimenti notes that while women can choose to freeze their eggs in order to increase their possibility of having children after cancer treatment, there are major risks involved.
"That is a serious dilemma and emotional issue," he explains, "when you layer a cancer diagnosis on top of the prospect of having permanent life-altering effects as a result of chemotherapy, and must face the urgent decision of delaying treatment to freeze oocytes at the risk of one's own life."
With this is mind, there is a desperate need to find strategies that can help to protect a woman's fertility during cancer treatment. The new study may have brought us one step closer to this feat.
CHK2 inhibitor protected oocytes in mice
In a 2014 study, Schimenti and colleagues found that radiotherapy-induced oocyte damage was associated with increased activity of the CHK2 protein in mice.
Further investigation revealed that CHK2 causes unrepairable DNA damage in oocytes; when mice lacking the CHK2 gene were exposed to radiation, their oocytes were able to repair the incurred DNA damage, and the rodents even gave birth to healthy pups.
In this latest study, the researchers set out to investigate whether the CHK2 pathway could be pharmacologically inhibited.
The team found that a CHK2 inhibitor called "CHK2iII," which is a small molecule previously tested as an anti-cancer drug, simulated the knockout of the CHK2 gene in female mice, effectively blocking the CHK2 pathway.
This drug prevented the oocytes of the mice from being destroyed by radiation exposure, the researchers report, and it allowed them to give birth to healthy pups.
Human studies needed
While the researchers are excited by these findings, they cannot rule out the possibility that the offspring of the treated mice might possess mutations in their oocytes as a result of their mother's radiation exposure.
"[...] even though these irradiated oocytes led to the birth of healthy mouse pups, it's conceivable that they harbor mutations that will become manifested in a generation or two, because we are circumventing an evolutionarily important mechanism of genetic quality control," explains Schimenti. "This needs to be investigated by genome sequencing."
Still, the team believes that their study indicates that it may one day be feasible to administer CHK2-inhibitors and cancer therapy simultaneously, as a means of protecting a woman's fertility.
However, the researchers stress that further studies are needed to establish the safety and efficacy of such a strategy in humans.
As Schimenti concludes, "While humans and mice have different physiologies, and there is much work to be done to determine safe and effective dosages for people, it is clear that we have the proof of principle for this approach."