Nov. 6, 2015 / by Jordana Lenon
A UW Health physician and her research team at UW-Madison have successfully tested a drug that prevents ovarian damage in adolescent mice exposed to chemotherapy and helps them have more and healthier offspring. The intervention also appears to increase survival rates in the treated mice.
The repurposed heart medication – Dexrazoxane, or Dexra for short – could save young lives while also overcoming current limitations to oncofertility treatments, reports Sana Salih, M.D., M.S., assistant professor of obstetrics and gynecology, School of Medicine and Public Health, in the scientific journal PLoS One today.
Salih and her research team originally set out only to find a way to safely protect the fertility of young female cancer patients. “Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” she says. “For prepubescent girls, the only option to prevent chemo-induced ovarian failure is ovarian tissue cryopreservation.” Unfortunately, she adds, this experimental procedure requires invasive surgeries, first to harvest and then to re-implant the tissue after successful cancer treatment. Transplantation of cryopreserved ovaries also carries with it a small risk of cancer recurrence. “In the end,” Salih says, “it provides only a short-term solution. The transplanted ovarian tissue has a limited function of only three to seven years.”
Salih was pleased to discover that pre-administration of Dexra diminished ovarian damage and preserved ovarian function and fertility in mice after their ovaries were exposed to the chemotherapy medication Doxorubicin (DXR).
“What really surprised us is that it took a very small dose of Dexra to give full ovarian protection,” Salih says. Mice treated with Dexra also gave birth to healthier litters, with more pups and larger birth weights than those only receiving DXR, she discovered.
Then came even more surprises: Dexra-protected mice given chemo lived much longer than mice given chemo only. Furthermore, mice given only Dexra lived longer than even control mice receiving no experimental interventions whatsoever.
“The FDA currently limits the use of Dexra to adults to protect their hearts from the toxic side effects of their chemotherapy drugs,” Salih said. “But these patients are receiving very high doses of Dexra. These doses may actually be contributing to increased toxicity overall, including secondary blood cancers and decreased survival in some of these patients.”
The researchers achieved high mouse survival rates, ovarian protection and birthing successes using a dose of Dexra 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues overall.
“This is all very exciting,” Salih said. “We are now submitting a grant to look at low-dose Dexra protection in live nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Salih, who also directs the Oncofertility Program in the School of Medicine and Public Health, is dedicated to performing the rigorous preclinical work required to show that safe doses of Dexra can protect developing primate ovaries. She wants to ensure that resulting nonhuman primate pregnancies produce healthy infants with normal birth weights, and that typical birth numbers remain intact. Nonhuman primate ovarian development, cycle time and gestation are very similar to that of humans. Earlier this year, to show proof of concept, she and her collaborators published mouse and marmoset ovarian tissue work in two separate papers in PLoS One and Biology of Reproduction.
“My goal is to present solid data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Salih said. “Up to six percent of young girls with childhood cancers and 50 percent of women with breast cancer enduring chemotherapy also have to face resulting ovarian failure. We need to lower this statistic and give more cancer survivors real hope that they can conceive a healthy child.”
Since chemotherapy is usually given as a combination of multiple drugs, Salih hopes that Dexra will be developed alongside other ovarian protection drugs in the future, to safely provide complete ovarian protection against multiple chemotherapy agents.
And now she has even more inspiration for her work, as shown by the surprising and dramatic survival rates her drug of choice bestowed on her study mice.
“The future of this research is to find more ways to protect not only the ovaries, but other tissues and organs as part of cancer treatment as well, to increase overall survival rates,” she says.
The paper’s coauthors include Jenna Kropp, Ph.D., Elon C. Roti Roti, Ph.D., and Ashley Ringelsterre, B.S., all in Salih’s lab at the Wisconsin National Primate Research Center. Also on the paper are Hasan Khatib, Ph.D., professor of animal sciences, College of Agricultural and Life Sciences, and David Abbott, Ph.D., professor of obstetrics and gynecology and scientist at the Primate Center. A Wisconsin Alumni Research Foundation grant, NIH Training Award, and University of Wisconsin Cancer Center Support Grant funded the research.