Pre-clinical Trials for Female Fertility Preservation

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DESCRIPTION (provided by applicant): Early ovarian failure and infertility are well-known side effects of anti-cancer treatments. While the need for tumor eradication is clear, the long-term consequences of these treatments on non-target tissues, such as the ovaries, are substantial. Unfortunately, attempts to preserve fertility and ovarian function in female cancer patients have met with little success. In studies with mice, we have shown that sphingosine-1- phosphate (S1P), a metabolite of the pro-apoptotic stress sensor ceramide, completely protects the ovaries from radiation-induced damage in vivo. Long-term in vivo mating trials have further shown that S1P preserves a normal level of fertility in irradiated female mice, and that offspring conceived with oocytes protected from radiation by S1P in vivo show no evidence of transgenerational genomic damage. With the use of a human ovarian-mouse xenograft model, we have also shown that injecting S1P directly into ovarian tissue can prevent radiation-induced loss of human primordial and primary follicles in vivo. Although these findings support that S1P-based strategies could be developed to combat infertility and ovarian failure, two major points still need to be addressed. The first is to establish the safety and efficacy of S1P for preserving ovarian function and fertility in non-human primates exposed to anti-cancer treatments. The second is to validate technologies to deliver S1P only to the ovaries, thereby preventing systemic availability of S1P that could benefit the tumor cells targeted for destruction. To accomplish these goals, the following Specific Aims are proposed: (1) to determine if S1P can be administered directly into the rhesus monkey ovary as a means to protect the gonads from radiotherapy-induced damage in vivo; (2) to evaluate the competency of the oocytes protected from radiotherapy by S1P in the non-human primate ovary for fertilization and embryogenesis; and (3) to assess if offspring conceived from non-human primate oocytes protected from radiotherapy by S1P in vivo show evidence of propagated genomic damage. The goal of our work is to develop safe and effective strategies for protecting human ovaries in vivo from the side-effect damage caused by anti-cancer therapies. We believe that the published and preliminary data discussed herein strongly support the need for now evaluating the efficacy of, as well as the delivery mechanisms for, S1P in this regard using the non-human primate as a model.