Cancer therapies inflict irreversible ovarian damage and deplete the finite reserve of oocytes, often causing infertility and premature menopause in female survivors. Unfortunately, current fertility preservation options have significant drawbacks, with no strategies available to protect both fertility and long-term endocrine function1. In landmark studies, our team revealed chemotherapy directly damages oocyte DNA, inducing apoptosis2. The apoptotic protein PUMA is chiefly responsible for triggering this, as genetic loss of Puma confers striking oocyte protection and preserves fertility in mice post-chemotherapy3. Excitingly, a small-molecule PUMA inhibitor (PUMAi) is now available, making targeting PUMA for fertility preservation a real therapeutic possibility.
To establish whether PUMAi prevents oocyte apoptosis during chemotherapy exposure, human ovarian cortical pieces (n=5 patients) were cultured with cyclophosphamide derivative 4-HC (2µM) ± PUMAi (200µM). Whilst 4-HC alone decreased primordial follicles (p<0.0001); remarkably, PUMAi treatment restored this significantly (p<0.05). Next, mice (n=6/group) received a fertility-damaging cyclophosphamide dose (150mg/kg) ± PUMAi (10mg/kg) 2h before/20h after; a regimen that prevents chemotherapy-induced gut toxicity4. Cyclophosphamide alone reduced primordial follicles by 75% (p<0.01); however, PUMAi rescued 25% of follicles (p<0.05). This is extremely promising, as protection of just 12% of follicles in Puma-/- mice sustains fertility, without compromising offspring health3,5.
To examine if PUMAi preserves fertility and offspring health, mice (n=10/group) received cyclophosphamide ± PUMAi (as above), and were mated with unexposed males for 3 litters. Though average litter sizes were similar, cyclophosphamide alone impacted offspring health, with only 28% of pups surviving past PN5 (p<0.001). PUMAi dramatically improved survival (54%; p<0.05), suggesting oocyte quality and offspring health are effectively preserved.
These data demonstrate PUMA blockade is a promising oncological fertility preservation avenue. Further studies are underway to ensure PUMAi does not impact chemotherapy efficacy using patient-derived organoids and in vivo tumour models, and determine whether multi-organ protection is conferred, beyond the reproductive tract.