FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

Simple Summary Late diagnosis of ovarian cancer is a major reason for the high mortality rate of this tumor entity. The time to determine tumor susceptibility to treatment is scarce and resistance to therapy occurs very frequently. Here, we aim for a model system that can determine tumor response to (I) study novel drugs and (II) enhance patient stratification. Tissue specimens (n = 10) were acquired from fresh surgical samples. Tissue cultures were cultivated and treated with clinically relevant therapeutics and an FOXM1 inhibitor for 3-6 days. The transcription factor FOXM1 is a key regulator of tumor survival affecting multiple cancerogenic target genes. Gene expression of FOXM1 and its targets BRCA1/2 and RAD51 were investigated together with tumor susceptibility. Tissue cultures successfully demonstrated the individual benefit of FOXM1 inhibition and revealed the potency of the complex model system for oncological research. Diagnosis in an advanced state is a major hallmark of ovarian cancer and recurrence after first line treatment is common. With upcoming novel therapies, tumor markers that support patient stratification are urgently needed to prevent ineffective therapy. Therefore, the transcription factor FOXM1 is a promising target in ovarian cancer as it is frequently overexpressed and associated with poor prognosis. In this study, fresh tissue specimens of 10 ovarian cancers were collected to investigate tissue cultures in their ability to predict individual treatment susceptibility and to identify the benefit of FOXM1 inhibition. FOXM1 inhibition was induced by thiostrepton (3 mu M). Carboplatin (0.2, 2 and 20 mu M) and olaparib (10 mu M) were applied and tumor susceptibility was analyzed by tumor cell proliferation and apoptosis in immunofluorescence microscopy. Resistance mechanisms were investigated by determining the gene expression of FOXM1 and its targets BRCA1/2 and RAD51. Ovarian cancer tissue was successfully maintained for up to 14 days ex vivo, preserving morphological characteristics of the native specimen. Thiostrepton downregulated FOXM1 expression in tissue culture. Individual responses were observed after combined treatment with carboplatin or olaparib. Thus, we successfully implemented a complex tissue culture model to ovarian cancer and showed potential benefit of combined FOXM1 inhibition.

Automated summary

Late diagnosis and resistance to therapy are major reasons for the high mortality rate of ovarian cancer. A model system was developed to predict individual treatment susceptibility and the potential benefit of FOXM1 inhibition in ovarian cancer was demonstrated through tissue cultures.