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Purpose Is it possible to eliminate metastasised chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cells from ovarian cortex fragments by inhibition of Aurora B/C kinases (AURKB/C) without compromising ovarian tissue or follicles? Methods Human ovarian cortex tissue with experimentally induced tumour foci of CML, AML and primary cells of AML patients were exposed to a 24h treatment with 1 μM GSK1070916, an AURKB/C inhibitor, to eliminate malignant cells by invoking mitotic catastrophe. After treatment, the inhibitor was removed, followed by an additional culture period of 6 days to allow any remaining tumour cells to form new foci. Ovarian tissue integrity after treatment was analysed by four different assays. Appropriate controls were included in all experiments. Results Foci of metastasised CML and AML cells in ovarian cortex tissue were severely affected by a 24h ex vivo treatment with an AURKB/C inhibitor, leading to the formation of multi-nuclear syncytia and large-scale apoptosis. Ovarian tissue morphology and viability was not compromised by the treatment, as no significant difference was observed regarding the percentage of morphologically normal follicles, follicular viability, glucose uptake or in vitro growth of small follicles between ovarian cortex treated with 1 μM GSK1070916 and the control. Conclusion Purging of CML/AML metastases in ovarian cortex is possible by targeting the Mitotic Catastrophe Signalling Pathway using GSK1070916 without affecting the ovarian tissue. This provides a therapeutic strategy to prevent reintroduction of leukaemia and enhances safety of autotransplantation in leukaemia patients currently considered at high risk for ovarian involvement.

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Objective: To assess the use of tumor-specific designed ankyrin repeat proteins (DARPins) fused to a domain of Pseudomonas aeruginosa exotoxin A for purging of cancer metastases from the ovarian cortex. Design: Experimental study. Setting: University medical center. Patient(s): Human ovarian cortex. Intervention(s): Ovarian cortex harboring artificially induced breast cancer metastases was treated with DARPins targeted to epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor 2 (HER2). Main Outcome Measure(s): The presence of any remaining cancer cells after purging was analyzed by (immuno)histochemistry and reverse transcriptase polymerase chain reaction. Effects on the viability of the ovarian cortex were determined by (immuno)histology, a follicular viability assay, and an assay to determine the in vitro growth capacity of small follicles. Result(s): After purging with EpCAM-targeted DARPin, all EpCAM-positive breast cancer cells were eradicated from the ovarian cortex. Although treatment had no effect on the morphology or viability of small follicles, a sharp decrease in oocyte viability during in vitro growth was observed, presumably due to low-level expression of EpCAM on oocytes. The HER2-targeted DARPins had no detrimental effects on the morphology, viability, or in vitro growth of small follicles. HER2-positive breast cancer foci were fully eliminated from the ovarian cortex, and the reverse transcriptase polymerase chain reaction showed a decrease to basal levels of HER2 mRNA after purging. Conclusion(s): Purging cancer metastases from ovarian cortex without impairing ovarian tissue integrity is possible by targeting tumor cell surface proteins with exotoxin A-fused DARPins. By adapting the target specificity of the cytotoxic DARPin fusions, it should be possible to eradicate metastases from all types of malignancies. (Fertil Steril Sci Ò 2021;2:330-44. Ó2021 by American Society for Reproductive Medicine.

Restoration of fertility by autologous transplantation of ovarian cortex tissue in former cancer patients may lead to the reintroduction of malignancy via the graft. Pharmacological ex vivo purging of ovarian cortex fragments prior to autotransplantation may reduce the risk of reseeding the cancer. In this study we have investigated the capacity of Everolimus (EVE), an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, to eradicate Ewing’s sarcoma (ES) from ovarian tissue by a short-term ex vivo treatment. Exposure of experimentally induced ES tumor foci in ovarian tissue to EVE for 24 h completely eliminated the malignant cells without detrimental effects on follicle morphology, survival or early folliculogenesis. This indicates that effective purging of ovarian cortex tissue from contaminating ES tumor foci is possible by short-term exposure to EVE.