Irreversible ovarian damage and depletion of oocytes are devastating side effects of many cancer treatments; often leaving female cancer survivors infertile and at risk of premature menopause. Unfortunately, current fertility preservation options have significant drawbacks, with no strategies available to protect both fertility and long-term endocrine function in young girls and women receiving cancer treatment. PUMA, an apoptotic protein, triggers oocyte death following exposure to DNA-damaging insults, like chemotherapy. In fact, genetic loss of PUMA preserves fertility post-chemotherapy without compromising offspring health. Excitingly, a small molecule PUMA inhibitor (PUMAi) has recently become available, making PUMA blockade for fertility preservation a real therapeutic possibility for the first time.
To assess whether PUMA blockade can prevent oocyte apoptosis post-chemotherapy, postnatal day 5 C57BL6/J ovaries were cultured ex vivo for 5 days in media containing the cyclophosphamide metabolite 4-HC (2µM) ± PUMAi (200µM). Whilst 4-HC alone significantly depleted primordial follicles by 85% (p<0.01), primordial follicle numbers in ovaries from the 4-HC+PUMAi group were not significantly different from controls. Next, adult mice were administered 10mg/kg PUMAi 2 hours before and 20 hours after 150mg/kg cyclophosphamide. This regimen was based on a previous study in which PUMAi prevented intestinal stem cell apoptosis post-chemotherapy. Remarkably, primordial follicle numbers were approximately doubled in the cyclophosphamide + PUMAi group versus cyclophosphamide alone (858±122 vs. 386±106, p<0.05). This is extremely promising, as genetic knockout models of PUMA prove that partial protection of just 12% of follicles sustains female fertility.
Collectively, these data demonstrate that PUMA blockade is a promising avenue for fertility preservation prior to chemotherapy treatment. Further studies are already underway to optimise the PUMAi regimen for maximal ovarian protection; ensure that PUMAi does not impact the anti-tumour efficacy of chemotherapy treatment; and to determine whether PUMAi can prevent primordial follicle apoptosis in vitro in human ovarian tissue.