Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. Patients with OCS are routinely treated with the standard of care therapies used for high-grade serous ovarian cancer (HGSOC), however, consistently have a worse outcome (Brackmann et al, 2018 and Hollis et al, 2022). The Scott laboratory have developed several unique cell line and organoid models from patient derived xenograft (PDX) models of OCS. Using these tools, we aim to identify novel combination therapies to more effectively treat OCS.
OCS are composed of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components (Rauh-Hain et al. 2016). We and others have provided recent evidence that these tumours arise from a single progenitor cell, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT) (del Carmen et al. 2012, Ho et al. 2022). These tumours also commonly harbour upregulation of the N-MYC/LIN28B pathway, resulting in high expression of the EMT marker HMGA2 (expressed in 60% of OCS – Helland et al. 2014). The microtubule-targeting drug eribulin has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas (Funahashi et al. 2014). We have previously shown that eribulin can also reverse EMT in our preclinical models of OCS (Ho et al. 2022). We have performed drug library and CRISPR screens alone and in combination with cisplatin (current treatment for HGSOC) and eribulin, with a focus on drugs that could potentially reverse EMT and/or target N-MYC, to identify new potential combination therapies for these tumours. Our results suggest that eribulin-based targeted combination therapy may improve patient outcomes for these aggressive malignancies.