Purging human ovarian cortex of contaminating leukaemic cells by targeting the mitotic catastrophe signalling pathway

Lotte Eijkenboom,Callista Mulder,Julia Van Leersum,Thessa Koorenhof-Scheele,Norah Van Mello,Bert Van Der Reijden,Didi Braat,Catharina Beerendonk,Ronald Peek

doi:10.1007/s10815-021-02081-9

Abstract

PurposeIs 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?MethodsHuman 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.ResultsFoci 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.ConclusionPurging 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.

Highlights

With the increase in overall 5-year survival rates in cancer [8, 70] due to advances in early detection and treatment, the effect on fertility of anti-cancer treatment has been gaining growing attention
We have investigated the use of GSK1070916, a reversible and ATP competitive inhibitor of Aurora B and Aurora C kinases (AURKB/C), to purge ovarian cortex tissue fragments contaminated with foci of chronic myeloid leukaemia (CML) or acute myeloid leukaemia (AML) from cell lines and of primary cancer cells from patients with AML
AURKB expression was not detected in ovarian cortex tissue or testicular tissue, while AURKC was abundantly expressed in testicular tissue and at low levels in ovarian tissue (Fig. 1)

Summary

Introduction

With the increase in overall 5-year survival rates in cancer [8, 70] due to advances in early detection and treatment, the effect on fertility of anti-cancer treatment has been gaining growing attention. As both radiotherapy and chemotherapy regimens can lead to subfertility or even infertility [31, 67, 73], the options for fertility preservation should be discussed before start of therapy. Multiple options are available for fertility preservation in women, for prepubertal girls and women who cannot delay start of their anti-cancer treatment ovarian tissue cryopreservation (OTC) is currently the sole option [13]. Live birth rates per autotransplantation are ranging from 23% up to 69% [20, 71]

Methods

Results

Conclusion