Each year, an estimated 13,000 American women under the age of 40 are diagnosed with breast cancer. It’s an age when worries of survival are compounded by worries of reproductive survival, because while cancer treatments can save lives, they can also leave women permanently infertile. That heartbreaking reality inspired reproductive endocrinologist Kara N. Goldman, MD, to pursue a solution in 2014, during a research fellowship at NYU Langone Health. “Patients, including young girls, face devastating choices as they try to balance cancer treatment against their ability to have children in the future,” says Dr. Goldman, assistant professor of obstetrics and gynecology, who treats patients at NYU Langone’s Fertility Center. “We need more options.”
Working with an interdisciplinary team of investigators, Dr. Goldman has plucked hope from an unlikely source: an immunosuppressant drug used to prevent organ rejection in transplant patients and even treat some cancers. Using female mice as a model, the researchers have shown that administering a drug called everolimus alongside chemotherapy protects the animals’ ovaries and preserves their fertility. The study appears in Proceedings of the National Academy of Sciences.
Currently, women diagnosed with cancer can elect to freeze their eggs or embryos prior to starting chemotherapy. That approach, however, has its limitations: the procedure is expensive and invasive, requiring hormonal stimulation and surgical retrieval of mature oocytes. “And it only works about 50 percent of the time,” says study coauthor David Keefe, MD, the Stanley H. Kaplan Professor of Obstetrics and Gynecology, chair of the Department of Obstetrics and Gynecology, and professor of cell biology at NYU Langone. “So a patient can lay out $15,000 and undergo 6 weeks of extensive exposure to hormones to find it didn’t work.” Many women can’t afford the procedure—or the delay in treating their cancer.
Chemotherapy attacks a woman’s reserve of eggs on two fronts. Women are born with a finite number of oocytes—1 million to 2 million, each encased in a protective follicle. By puberty, about 300,000 remain. During each menstrual cycle, a small clutch of these primordial follicles begins to develop “like a faucet set on trickle,” explains Dr. Keefe. One of the maturing follicles will release its egg during ovulation, and the others will degenerate. Chemotherapy agents, which kill rapidly dividing tumor cells, also destroy these actively growing follicles. The ovaries overcompensate “so the trickle of follicles becomes a gush,” adds Dr. Keefe. That overreaction can lead to infertility by prematurely depleting a woman’s ovarian reserve—an effect dubbed “follicular burnout.”
A 2008 study from the Karolinska Institute revealed that this follicular activation is regulated by a signaling pathway known as mTOR, which helps direct cellular growth. Blocking that pathway with an mTOR inhibitor like everolimus, the investigators reasoned, should dampen this follicular overreaction and thereby block the adverse effects of chemotherapy.
That’s where Robert J. Schneider, PhD, comes in. Dr. Schneider, the Albert B. Sabin Professor of Microbiology and Molecular Pathogenesis, professor of radiation oncology, and associate dean for therapeutics alliances at NYU Langone, has spent years studying the role mTOR plays in breast cancer, and he was keen to explore whether the pathway could help preserve fertility.
“Our protocol was aligned as closely as possible with those used to treat humans,” says Dr. Schneider, a senior author on the study. “So an equivalent duration and dose of drugs, adjusted for the mouse.” What they saw was that mice treated with everolimus were left with up to three times as many follicles as those treated with the chemotherapy drug Cytoxan® alone. The treated animals also showed higher levels of anti-Mullerian hormone, a molecule that serves as a clinical marker of ovarian reserve in humans.
More important, the mTOR inhibitor preserved the animals’ fertility: treated mice gave birth to an average of seven pups, essentially the same number as those untreated. Mice treated with Cytoxan® alone had litters that were, on average, half the size, and a few produced no pups at all.
The treatment strategy could not only preserve fertility, but also enhance it, pointing to new therapies for healthy women struggling to conceive. Preliminary data show that the mTOR inhibitor, when given at an early age, can extend reproductivity in healthy young mice. “But those studies are very early,” cautions Dr. Schneider.
For now, the researchers are focused on translating their results to the clinic. “First, we need to demonstrate that mTOR inhibitors can preserve ovarian function in women,” says Dr. Goldman. To gather that data, she has contacted clinicians who are already treating women with mTOR inhibitors for tuberous sclerosis and lymphangioleiomyomatosis, rare conditions unrelated to infertility or cancer, so she can assess their ovarian reserve.
If all goes well, Dr. Goldman and team expect to launch a clinical trial in a year or so, an unusually speedy transition facilitated by the use of a medication already approved for other indications, and by the collaborative culture at NYU Langone. “Our research fellows really help improve the way we practice,” says study coauthor James A. Grifo, MD, PhD, professor of obstetrics and gynecology, director of the Division of Reproductive Endocrinology and Infertility, and director of NYU Langone’s Fertility Center. “Kara chose and executed a great project, and if we can turn this into something that results in a clinical tool, it will have a huge, huge impact.”