The research, “mTORC1/2 Inhibition Preserves Ovarian Function And Fertility During Genotoxic Chemotherapy,” was published in the journal PNAS.
A major concern for premenopausal women who have chemotherapy is infertility. That’s because the treatment can damage the ovaries and reduce the supply of ovarian follicles, precursors of egg cells that are needed for future pregnancies.
“Patients, including young girls, face devastating choices as they try to balance cancer treatment against their ability to have children in the future,” Kara Goldman, MD, the study’s first author, said in a news release. “We need more options.”
Researchers used female mice to test two drugs that might protect ovaries against damage from chemotherapy. One drug was Afinitor, which has been approved to fight tumor growth in some forms of kidney and breast cancer. The other therapy was INK128, an experimental drug being tested in clinical trials against several types of cancer.
Female mice receiving cyclophosphamide chemotherapy alone experienced a 64 percent reduction in ovarian follicles and produced fewer offspring, researchers found. Those that received chemotherapy in combination with everolimus or INK28 had normal ovarian reserves, follicle counts, and fertility, they discovered.
“Our results argue that everolimus may represent a fertility-sparing drug treatment to complement the freezing of eggs and embryos, which are valued methods, but time-consuming, costly, less effective with age, and not protective of long-term ovarian function,” Goldman said.
Everolimus and INK28 protect ovaries by inhibiting a molecular signaling pathway called mTOR, which is activated in cancer cells, promoting their proliferation. Although cyclophosphamide helps fight cancer cells, in the ovaries it promotes the activation of mTOR signaling, which stimulates ovarian follicles to mature and multiply. Then cyclophosphamide attacks their DNA, causing their death and leading to infertility.
By inhibiting mTOR signaling in ovaries, everolimus and INK28 may help preserve normal fertility in women receiving conventional chemotherapy for breast cancer.
“Only clinical trial results will tell whether these drugs can protect fertility and counter hormonal deficits naturally by preserving follicles,” said Robert Schneider, PhD, the study’s senior author. “Our goal is to complete studies on the best dose for ovarian preservation, and then to get everolimus into a trial for this use next year.”